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For decades, Alzheimer’s disease has been seen as the primary culprit behind age-related memory decline. However, researchers are now recognizing that other conditions can cause similar symptoms, particularly in older adults. A new study by Mayo Clinic scientists proposes criteria to identify a memory loss syndrome called limbic-predominant amnestic neurodegenerative syndrome (LANS). The condition mimics Alzheimer’s but is caused by different brain changes and may have a better prognosis.
The limbic system is a group of interconnected brain structures involved in memory, emotion, and behavior. In LANS, degeneration occurs primarily in these limbic areas rather than the broader brain regions affected in Alzheimer’s. This focused damage leads to memory problems that can be mistaken for early Alzheimer’s, but LANS tends to progress more slowly and spare other cognitive abilities.
“In our clinical work, we see patients whose memory symptoms appear to mimic Alzheimer’s disease, but when you look at their brain imaging or biomarkers, it’s clear they don’t have Alzheimer’s,” says senior author Dr. David T. Jones, a Mayo Clinic neurologist, in a statement. “Until now, there has not been a specific medical diagnosis to point to, but now we can offer them some answers.”
LANS vs. Alzheimer’s
The most common underlying cause of LANS is thought to be a recently recognized condition called limbic-predominant age-related TDP-43 encephalopathy (LATE). TDP-43 is a protein that, when misfolded, can accumulate in brain cells and cause damage. In LATE, TDP-43 buildup occurs mainly in limbic areas critical for memory. However, the researchers note that other causes are likely, and more research is needed.
Identifying LANS is crucial because it may require different treatments than Alzheimer’s. As new Alzheimer’s drugs hit the market, doctors need ways to determine which patients are likely to benefit. The proposed LANS criteria could help avoid giving these potentially risky and expensive medications to people unlikely to respond.
“Historically, you might see someone in their 80s with memory problems and think they may have Alzheimer’s disease, and that is often how it’s being thought of today,” says Dr. Nick Corriveau-Lecavalier, the paper’s first author. “With this paper, we are describing a different syndrome that happens much later in life. Often, the symptoms are restricted to memory and will not progress to impact other cognitive domains, so the prognosis is better than with Alzheimer’s disease.”
The study, published in Brain Communications, found that patients meeting LANS criteria tended to have slower cognitive decline than those with typical Alzheimer’s. Brain scans showed patterns of degeneration focused in memory-related limbic regions rather than the wider brain involvement seen in Alzheimer’s.
Interestingly, some patients had a mix of LANS and Alzheimer’s-related brain changes. Those with high LANS likelihood despite some Alzheimer’s pathology still showed slower decline, suggesting LANS may be the primary driver of their symptoms.
Diagnosing LANS
The researchers propose a set of core, standard, and advanced criteria for diagnosing LANS. Core criteria include a slow-progressing, predominantly memory-related decline. Standard criteria involve being over 75, having mild symptoms with mostly intact non-memory abilities, disproportionate shrinkage of memory-related brain areas, and specific types of memory impairment. Advanced criteria utilize brain scans and tests for Alzheimer’s-related proteins.
By combining these factors, doctors can determine if a patient has a low, moderate, high, or highest likelihood of having LANS. This could guide treatment decisions and help set expectations about disease progression. “This research creates a precise framework that other medical professionals can use to care for their patients,” says Jones. “It has major implications for treatment decisions, including amyloid-lowering drugs and new clinical trials, and counseling on their prognosis, genetics and other factors.”
As research on LANS and LATE progresses, these criteria may evolve. However, they represent an important step toward recognizing the diverse causes of memory loss in older adults. This more nuanced understanding could lead to better diagnosis, prognosis, and eventually targeted treatments for different types of age-related cognitive decline.
Paper Summary
Methodology
The researchers analyzed data from two groups of deceased patients who had donated their brains for study – one from the Mayo Clinic and another from the Alzheimer’s Disease Neuroimaging Initiative. They focused on patients who had shown progressive memory problems in life and had either Alzheimer’s, LATE, or both conditions found at autopsy. The study included data from more than 200 participants in databases for the Mayo Clinic Alzheimer’s Disease Research Center, the Mayo Clinic Study of Aging, and the Alzheimer’s Disease Neuroimaging Initiative. They looked at various clinical, imaging, and biomarker data collected during the patients’ lives to see which factors best distinguished those with LATE from those with Alzheimer’s. This allowed them to develop and test their proposed LANS criteria.
Results
The LANS criteria effectively categorized patients based on their underlying brain pathology. Most patients with high LANS likelihood had LATE at autopsy, while those with low likelihood typically had Alzheimer’s. Patients with both conditions showed a range of likelihoods. Higher LANS likelihood was associated with slower cognitive decline and more focused degeneration in limbic brain regions on scans. A statistical model using the LANS criteria features correctly classified about 75% of patients as having LATE or not.
Limitations
The study had a relatively small number of patients with LATE alone, which limited some statistical comparisons. The criteria were developed and tested on patients who had already died, so prospective studies in living patients are needed to further validate their usefulness. The researchers also note that other rare conditions can cause LANS-like symptoms, so the criteria are not perfectly specific to LATE.
Discussion and Takeaways
The LANS criteria represent a significant step toward distinguishing memory loss caused by limbic degeneration from that caused by typical Alzheimer’s. This distinction is important for several reasons:
- It can help set more accurate expectations about disease progression, as LANS typically advances more slowly than Alzheimer’s.
- It may guide treatment decisions, particularly as new Alzheimer’s drugs become available that may not be effective for LANS.
- It provides a framework for future research into non-Alzheimer’s causes of memory loss in older adults.
- It highlights the complexity of age-related cognitive decline, showing that multiple pathologies often coexist and interact.
The researchers emphasize that these criteria are meant to be a starting point and will likely be refined as more is learned about LANS and LATE. They also note the need for biomarkers specific to TDP-43, the protein involved in LATE, to further improve diagnosis.
Funding and Disclosures
The study was funded by several sources, including National Institutes of Health grants P30 AG062677, P50 AG016574, U01 AG006786, R37 AG011378 and R01 AG041851, as well as the Robert Wood Johnson Foundation, the Elsie and Marvin Dekelboum Family Foundation, the Liston Family Foundation, the Edson Family, the Gerald A. and Henrietta Rauenhorst Foundation and the Foundation Dr. Corinne Schuler. Drs. Jones and Corriveau-Lecavalier reported no conflicts of interest, though a complete list of co-authors and financial disclosures is available in the manuscript.
