The article proposes a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome (LANS), which is characterized by progressive limbic system degeneration and associated clinical signs and symptoms. LANS is primarily associated with limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) but can also be linked to other neuropathologies. The criteria include core, standard, and advanced features such as older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degeneration, and low likelihood of neocortical tau pathology. These criteria were validated using clinical, imaging, and biomarker data from autopsied patients from the Mayo Clinic and Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts. The results show that the criteria effectively categorized patients with LATE-NC, Alzheimer’s disease neuropathological changes (ADNC), and comorbid ADNC/LATE-NC. Patients with higher LANS likelihoods had a slower clinical course and more severe temporo-limbic degeneration, while those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of these criteria has implications for distinguishing different aetiologies of progressive amnestic presentations, guiding diagnosis, prognosis, treatment, and clinical trials.The article proposes a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome (LANS), which is characterized by progressive limbic system degeneration and associated clinical signs and symptoms. LANS is primarily associated with limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) but can also be linked to other neuropathologies. The criteria include core, standard, and advanced features such as older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degeneration, and low likelihood of neocortical tau pathology. These criteria were validated using clinical, imaging, and biomarker data from autopsied patients from the Mayo Clinic and Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts. The results show that the criteria effectively categorized patients with LATE-NC, Alzheimer’s disease neuropathological changes (ADNC), and comorbid ADNC/LATE-NC. Patients with higher LANS likelihoods had a slower clinical course and more severe temporo-limbic degeneration, while those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of these criteria has implications for distinguishing different aetiologies of progressive amnestic presentations, guiding diagnosis, prognosis, treatment, and clinical trials.