New diagnostic guidelines aim to distinguish common memory disorder from Alzheimer’s

By Vijay Kumar MalesuReviewed by Danielle Ellis, B.Sc.Jan 28 2025

Penn Medicine-led research outlines criteria for limbic-predominant age-related TDP-43 encephalopathy, advancing clinical trials and treatment options for this common but underdiagnosed memory-loss syndrome

In a recent perspective published in Alzheimer's & Dementia, the authors established clinical diagnostic criteria for Limbic-Predominant Age-Related TDP-43 Encephalopathy Neuropathologic Change (LATE-NC) to differentiate it from Alzheimer's Disease Neuropathologic Change (ADNC), enhance recognition of amnestic syndromes, and assess its impact on therapeutic outcomes.

Background

LATE is a major cause of memory loss in older adults, affecting over 10% of individuals aged 65 and above and up to 40% of those over 85. LATE-NC commonly co-occurs with ADNC, accelerating cognitive decline when present together.

While LATE-NC progresses slowly when occurring alone, its differentiation from ADNC is critical, especially with emerging anti-amyloid therapies targeting AD. However, the absence of sensitive biomarkers and diagnostic guidelines for LATE-NC hinders accurate diagnosis and treatment. Further research is essential to address these gaps.

Prevalence and impact of LATE-NC

LATE-NC is highly prevalent in aging populations, particularly among individuals aged 85 and older, affecting approximately one-third of this demographic. Its presence contributes significantly to age-related memory loss, independent of ADNC. Importantly, co-pathology with LATE-NC has implications for emerging disease-modifying therapies, particularly those targeting amyloid and tau.

Identifying LATE-NC during life is crucial for accurate diagnosis and management, especially in the context of new therapeutics approved by regulatory agencies such as the United States (U.S.) Food and Drug Administration (FDA).

Challenges in differentiation from AD

Differentiating LATE-NC from ADNC poses a significant challenge due to overlapping clinical features, particularly in amnestic syndromes. Both conditions share a pattern of temporo-limbic memory loss, making it difficult to distinguish between them based on cognitive symptoms alone. In cases where LATE-NC is the primary pathology, the syndrome tends to progress more slowly than "pure" AD. However, when LATE-NC co-occurs with ADNC, the progression is more rapid, underscoring the importance of accurate differentiation for prognosis and treatment planning.

Diagnostic limitations and the need for biomarkers

Currently, there are no molecularly specific and sensitive biomarkers for TAR DNA-binding protein 43 (TDP-43) pathology, the hallmark of LATE-NC. Advances in amyloid and tau imaging have highlighted the need to develop comparable biomarkers for LATE-NC to facilitate its differentiation from ADNC. Imaging studies have shown promising patterns, such as hippocampal atrophy disproportionate to overall brain atrophy, but further validation is required. Without reliable biomarkers, clinicians must rely on clinical and neuroimaging features, which can be ambiguous, to make a diagnosis.

Clinical diagnostic criteria for LATE

To address these challenges, researchers have proposed clinical criteria for diagnosing LATE. These criteria distinguish between two scenarios: (1) LATE-NC as the primary driver of cognitive decline and (2) LATE-NC co-occurring with ADNC. For cases where LATE-NC is suspected as the primary pathology, a diagnosis of probable or possible LATE can be made based on clinical features, neuroimaging findings, and biomarker evidence.

Core features of LATE

The primary clinical feature of LATE is progressive episodic memory loss characterized by temporo-limbic amnesia. Patients exhibit significant deficits in delayed recall, which are not substantially improved with cueing or recognition memory. In contrast to frontal or subcortical memory impairments, temporo-limbic memory loss is associated with relatively preserved immediate memory. Other cognitive domains, such as executive function and visuospatial abilities, are typically spared in the early stages.

Neuroimaging support

Significant hippocampal atrophy, particularly in the medial temporal lobe, is a hallmark imaging feature of LATE-NC. This atrophy is often out of proportion to global brain atrophy and can help distinguish LATE-NC from other neurodegenerative conditions. Advanced imaging techniques, such as Fluorodeoxyglucose Positron Emission Tomography (FDG-PET), may reveal patterns of hypometabolism in the medial temporal lobe, further supporting the diagnosis.

Implications for treatment

The emergence of anti-amyloid therapies for AD has underscored the need to identify LATE-NC accurately. Patients with negative amyloid biomarkers may still exhibit significant cognitive decline due to LATE-NC, highlighting the potential for misclassification and suboptimal treatment. Additionally, the co-occurrence of LATE-NC and ADNC may influence the effectiveness of anti-amyloid therapies, emphasizing the importance of tailored treatment approaches.

Prognostic value of diagnosis

Accurate diagnosis of LATE-NC has significant prognostic implications. In cases where LATE-NC is the primary pathology, the disease course is generally indolent, allowing for more extended periods of preserved function. Conversely, patients with mixed pathology experience more rapid cognitive decline, necessitating more aggressive intervention and support.

Conclusions

To summarize, the study concludes that LATE-NC is a prevalent and significant contributor to memory decline in older adults, often co-occurring with ADNC. Accurate diagnosis of LATE-NC is critical, particularly as anti-amyloid therapies for AD become more widespread. The proposed clinical criteria offer a framework to differentiate LATE-NC from ADNC and to identify individuals with mixed pathology. However, the absence of specific biomarkers for TDP-43 limits diagnostic precision.