Summary: Researchers have defined clinical criteria for Limbic-predominant Amnestic Neurodegenerative Syndrome (LANS), a distinct memory-loss disorder that is frequently misdiagnosed as Alzheimer’s disease.
LANS typically advances more slowly than Alzheimer’s and carries a more favorable prognosis. The new criteria enable clinicians to identify LANS in living patients using clinical assessment, brain imaging and biomarker evidence, improving diagnosis, management and the ability to tailor treatment plans for people with age-related memory decline.
Key Facts:
- Distinct syndrome: LANS presents as an amnestic disorder centered on the limbic system and can be mistaken for Alzheimer’s disease, but its progression is generally slower.
- Clinical criteria: The newly proposed criteria allow diagnosis during life by combining age, memory impairment profile, hippocampal and temporo-limbic imaging, and biomarker patterns.
- Better prognosis: Patients who meet high-likelihood criteria for LANS show milder decline and slower progression than typical Alzheimer’s patients.
Source: Mayo Clinic
Researchers at Mayo Clinic have published a validated set of clinical criteria for an amnestic syndrome that predominantly affects the brain’s limbic structures, clarifying a condition previously confirmed only at autopsy.
Limbic-predominant Amnestic Neurodegenerative Syndrome (LANS) is now more clearly defined for clinicians. Unlike typical Alzheimer’s disease, this syndrome often presents later in life, primarily impairs episodic memory, and follows a slower clinical course. Defining LANS with standardized criteria gives doctors a practical framework to diagnose and counsel patients, and it helps guide decisions about therapies and clinical trial eligibility.
Before these criteria were proposed and validated in Brain Communications, confirmation of the underlying pathology often required post-mortem brain examination. The new framework uses a combination of core, standard and advanced clinical features—older age at evaluation, a predominantly amnestic syndrome of mild severity, disproportionate hippocampal atrophy on MRI, impaired semantic memory, limbic hypometabolism on functional imaging, and biomarker patterns that argue against widespread neocortical tau pathology.
The criteria were developed and tested using data from more than 200 participants drawn from the Mayo Clinic Alzheimer’s Disease Research Center, the Mayo Clinic Study of Aging and the Alzheimer’s Disease Neuroimaging Initiative. Researchers applied the criteria to patients who had undergone autopsy and compared antemortem clinical and imaging profiles with neuropathologic diagnoses, including Alzheimer’s disease neuropathologic change and limbic-predominant age-related TDP-43 encephalopathy (LATE).
David T. Jones, M.D., a Mayo Clinic neurologist and senior author, explains that in clinical practice many older adults present with memory symptoms that resemble Alzheimer’s, but their imaging and biomarker profiles suggest a different underlying process. “Until now, there has not been a specific medical diagnosis to point to, but now we can offer them some answers,” Jones says. He notes that the criteria have implications for treatment choices—such as whether amyloid-targeting therapies are appropriate—participation in clinical trials, and counseling about prognosis and genetics.
Nick Corriveau-Lecavalier, Ph.D., the paper’s first author, emphasizes that decades of work to separate different dementia syndromes are paying off. These criteria help distinguish LANS from neocortical degenerative syndromes that often require different therapeutic approaches and have different expected courses. “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,” he says.
The investigators focused on TDP-43 proteinopathy as one likely contributor to the limbic-predominant syndrome. Accumulations of TDP-43 in limbic structures have been identified in autopsied brains of older adults and are classified as limbic-predominant age-related TDP-43 encephalopathy (LATE). While LATE appears strongly associated with the LANS clinical profile, the authors caution that other pathologic processes can produce similar presentations and further research is necessary to refine specific biomarkers.
In validation analyses, the criteria categorized neuropathology-defined groups effectively: Alzheimer’s disease cases tended to show the lowest likelihood of LANS, LATE cases the highest likelihood, and mixed pathology cases intermediate likelihoods. A logistic regression model using the criteria features achieved balanced accuracy above 70% in both development and external cohorts. Patients classified with higher likelihoods for LANS showed more pronounced temporo-limbic degeneration but a milder, slower clinical decline compared with those at lower likelihood.
Establishing operational clinical criteria for LANS can help clinicians differentiate causes of progressive amnestic presentations in older adults, provide more accurate prognostic information, guide appropriate treatment choices, and improve patient selection for clinical trials focused on age-related limbic proteinopathies.
Funding: The research received partial support from National Institutes of Health grants P30 AG062677, P50 AG016574, U01 AG006786, R37 AG011378 and R01 AG041851, and from 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. A full list of co-authors and financial disclosures is provided in the published manuscript.
About this LANS, memory, and aging research news
Author: Emily DeBoom ([email protected])
Source: Mayo Clinic
Contact: Emily DeBoom – Mayo Clinic
Image: The image is credited to Neuroscience News
Original Research: Open access. “Clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome” by David T. Jones et al., published in Brain Communications.
Abstract
Clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome
Predominant limbic degeneration is linked to several underlying pathologies, typically occurs at older ages, and presents mainly as impaired episodic memory with slow progression. Until now, however, a distinct clinical syndrome associated with this pattern of limbic-predominant degeneration had not been defined.
Clearly delineating this syndrome is important to separate it from conditions driven by neocortical degeneration, which can differ substantially in cause, clinical course and treatment needs. The authors propose a tiered set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome that is strongly associated with limbic-predominant age-related TDP-43 encephalopathy (LATE), though other pathologies may also underlie the syndrome.
The criteria include core, standard and advanced features—older age at assessment, a mild, predominantly amnestic clinical presentation, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of widespread neocortical degeneration, and low likelihood of neocortical tauopathy—organized into degrees of certainty (highest, high, moderate and low).
These criteria were operationalized and validated using clinical, imaging and biomarker data from autopsied patients in Mayo Clinic and Alzheimer’s Disease Neuroimaging Initiative cohorts who had antemortem amnestic syndromes and postmortem diagnoses of Alzheimer’s disease neuropathologic change, LATE, or both. In the Mayo cohort (n = 165) and the ADNI cohort (n = 53), neuropathology-defined groups composed 35%, 37% and 4% of cases (Mayo) and 30%, 22% and 9% of cases (ADNI) for Alzheimer’s disease, LATE and mixed pathology, respectively.
Application of the criteria distinguished these groups: LATE cases had the highest likelihoods, Alzheimer’s cases the lowest, and mixed pathology cases intermediate likelihoods. A predictive model using the criteria features achieved balanced accuracy of 74.6% in the Mayo cohort and 73.3% in an external cohort. Patients with higher likelihoods exhibited more severe temporo-limbic degeneration but a milder, slower clinical decline. The criteria therefore provide a practical means to disambiguate amnestic syndromes in older adults and to guide diagnosis, prognosis, treatment and trial enrollment.