A New Type of Memory Loss in Older Adults
2025 marks the 50th anniversary of SNL (Saturday Night Live), and it’s been celebrated with specials, callbacks, and retrospective skits that strike a strangely nostalgic chord. The season blends humor, nostalgia, and wistfulness, mixing memory and emotion in a rare way. This emotional response lights up the Limbic System in the brain, an evolutionarily ancient set of brain structures that link emotion, memory, and behavior [1, 2]. Newer SNL cast members often talk about how their work is informed and built on the backs of earlier comedians and writers, just like our sense of self is built on a string of related memories. When our limbic system and the memories contained within fail us, it’s no laughing matter.
Memory problems during old age are common, but the exact causes of memory loss are still being investigated. Tau tangles and amyloid plaques, common in Alzheimer’s disease, can cause the destruction of cells all over the brain, including memory cells [3, 4]. Recently, researchers have described a different syndrome that targets the limbic system specifically [4]. Limbic-predominant Amnestic Neurodegenerative Syndrome (LANS) is a condition affecting memory loss while keeping the rest of the brain relatively intact [4]. LANS is characterized by a loss of episodic memory [4]. Episodic memories relate to specific events in your past and differ from semantic memories, things like facts, dates, and the names of objects. Forgetting that I watched the latest episode of SNL is a lapse in episodic memory; forgetting what “SNL” stands for is a lapse in semantic memory.
LANS affects people later in life, typically those over 75 years old [4]. There’s no evidence that gender plays a role in its development, but there is scarce information on the risks of developing LANS [4]. The onset is much slower than with Alzheimer’s, taking multiple years. Behind the scenes, the limbic system, which is deeper towards the center of the brain, is weakened and degrades while keeping the wrinkled surface (where our complex problem-solving occurs) relatively intact (though other conditions can disrupt these higher areas) [4, 5, 6]. This is an emerging syndrome, so researchers are still investigating the exact specifics.
Parts of the limbic system
The primary suspect in LANS is a protein in the brain called Transactive response DNA binding Protein-43 (TDP-43) [4, 5]. TDP-43 regulates which genes become proteins in the limbic system and can misfold (a type of mutation) and start accumulating outside of its normal location, leading to big problems [7, 8]. Misfolded TDP-43 seems to cause limbic structures to harden and waste away, resulting in the memory problems we see with LANS [6, 7]. TDP-43 accumulations outside of the limbic system have been associated with other brain problems, including Alzheimer’s and ALS (also known as Lou Gehrig's disease) [6, 4, 7, 8].
LANS is still very new, so it needs a lot more research. There is currently no way to definitively test for TDP-43 or LANS, so diagnosis requires looking for the clinical symptoms and ruling out other possible diseases. Patients display lower Mini-mental state examination (MMSE) scores, lower episodic memory scores, preserved higher-order thinking, and a slower onset of symptoms [4, 6]. LANS can occur along with other diseases of aging, making specific diagnoses very challenging [5, 7]. More research in this emerging area is critical as the US population ages [5]. Current memory medications are almost entirely aimed at the biomarkers associated with Alzheimer’s, including tau and amyloid beta, which may not work for patients with LANS and TDP-43 abnormalities [1, 5]. If clinical trials and other research can find better diagnostic criteria and biomarkers, medications to target LANS may be found before SNL’s 100th Anniversary Special.
Creative Director Benton Lowey-Ball, BS, BFA
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References:
[1] Morgane, P. J., Galler, J. R., & Mokler, D. J. (2005). A review of systems and networks of the limbic forebrain/limbic midbrain. Progress in neurobiology, 75(2), 143-160. https://www.sciencedirect.com/science/article/pii/S030100820500002X
[2] Catani, M., Dell’Acqua, F., & De Schotten, M. T. (2013). A revised limbic system model for memory, emotion and behaviour. Neuroscience & Biobehavioral Reviews, 37(8), 1724-1737. https://www.sciencedirect.com/science/article/pii/S0149763413001711
[3] Knopman, D. S., Amieva, H., Petersen, R. C., Chételat, G., Holtzman, D. M., Hyman, B. T., ... & Jones, D. T. (2021). Alzheimer disease. Nature reviews Disease primers, 7(1), 33. https://www.nature.com/articles/s41572-021-00269-y
[4] Corriveau-Lecavalier, N., Botha, H., Graff-Radford, J., Switzer, A. R., Przybelski, S. A., Wiste, H. J., ... & Jones, D. T. (2024). Clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome. Brain Communications, 6(4). https://academic.oup.com/braincomms/article/6/4/fcae183/7712717
[5] Wolk, D. A., Nelson, P. T., Apostolova, L., Arfanakis, K., Boyle, P. A., Carlsson, C. M., ... & Schneider, J. A. (2024). Clinical criteria for Limbic‐Predominant age‐related TDP‐43 encephalopathy. Alzheimer's & Dementia, e14202. https://alz-journals.onlinelibrary.wiley.com/doi/pdf/10.1002/alz.14202
[6] Nelson, P. T., Dickson, D. W., Trojanowski, J. Q., Jack, C. R., Boyle, P. A., Arfanakis, K., ... & Schneider, J. A. (2019). Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain, 142(6), 1503-1527. https://academic.oup.com/brain/article/142/6/1503/5481202
[7] Tremblay, C., St-Amour, I., Schneider, J., Bennett, D. A., & Calon, F. (2011). Accumulation of transactive response DNA binding protein 43 in mild cognitive impairment and Alzheimer disease. Journal of Neuropathology & Experimental Neurology, 70(9), 788-798. https://pmc.ncbi.nlm.nih.gov/articles/PMC3197017/
[8] Mackenzie, I. R., Neumann, M., Baborie, A., Sampathu, D. M., Du Plessis, D., Jaros, E., ... & Lee, V. M. (2011). A harmonized classification system for FTLD-TDP pathology. Acta neuropathologica, 122, 111-113. https://pmc.ncbi.nlm.nih.gov/articles/PMC3285143/
