A clinical criteria set for a limbic-predominant amnestic neurodegenerative syndrome (LANS) has been proposed, which is highly associated with limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) but also other pathologic entities. 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. These criteria were validated using clinical, imaging, and biomarker data from the Mayo Clinic and Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts. The criteria effectively categorized cases, with LATE-NC having the highest likelihoods, ADNC the lowest, and ADNC/LATE-NC intermediate. Logistic regression using the criteria features as predictors of TDP-43 achieved a balanced accuracy of 74.6% in the Mayo cohort and 73.3% in an external cohort. Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying ADNC/LATE-NC patients according to their likelihoods revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of decline, while those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of LANS criteria has implications for distinguishing different aetiologies of progressive amnestic presentations in older age and guiding diagnosis, prognosis, treatment, and clinical trials. The criteria were operationalized using clinical, imaging, and biomarker data and validated in two cohorts. The criteria are not meant for clinical practice but to provide construct validity. The study highlights the importance of distinguishing between limbic and neocortical degeneration in clinical practice, as they may differ in underlying aetiology, disease course, and therapeutic needs. The findings suggest that LANS is characterized by a relatively isolated amnestic syndrome with an indolent progression compared to ADNC, in addition to semantic memory impairment. In vivo neuroimaging markers of autopsy-confirmed LATE-NC have been described, including hippocampal atrophy and limbic hypometabolism. FDG-PET has also been proven useful for delineating patterns of involvement associated with LATE-NC. The study provides a framework for identifying and distinguishing LANS from other amnestic syndromes, which is critical for accurate diagnosis and treatment. The results suggest that LANS is a distinct clinical entity with a unique pattern of degeneration and clinical features, which can be used to guide clinical decision-making. The study also highlights the importance of considering the underlying pathology when diagnosing amnestic syndromes, as different pathA clinical criteria set for a limbic-predominant amnestic neurodegenerative syndrome (LANS) has been proposed, which is highly associated with limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) but also other pathologic entities. 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. These criteria were validated using clinical, imaging, and biomarker data from the Mayo Clinic and Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts. The criteria effectively categorized cases, with LATE-NC having the highest likelihoods, ADNC the lowest, and ADNC/LATE-NC intermediate. Logistic regression using the criteria features as predictors of TDP-43 achieved a balanced accuracy of 74.6% in the Mayo cohort and 73.3% in an external cohort. Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying ADNC/LATE-NC patients according to their likelihoods revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of decline, while those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of LANS criteria has implications for distinguishing different aetiologies of progressive amnestic presentations in older age and guiding diagnosis, prognosis, treatment, and clinical trials. The criteria were operationalized using clinical, imaging, and biomarker data and validated in two cohorts. The criteria are not meant for clinical practice but to provide construct validity. The study highlights the importance of distinguishing between limbic and neocortical degeneration in clinical practice, as they may differ in underlying aetiology, disease course, and therapeutic needs. The findings suggest that LANS is characterized by a relatively isolated amnestic syndrome with an indolent progression compared to ADNC, in addition to semantic memory impairment. In vivo neuroimaging markers of autopsy-confirmed LATE-NC have been described, including hippocampal atrophy and limbic hypometabolism. FDG-PET has also been proven useful for delineating patterns of involvement associated with LATE-NC. The study provides a framework for identifying and distinguishing LANS from other amnestic syndromes, which is critical for accurate diagnosis and treatment. The results suggest that LANS is a distinct clinical entity with a unique pattern of degeneration and clinical features, which can be used to guide clinical decision-making. The study also highlights the importance of considering the underlying pathology when diagnosing amnestic syndromes, as different path