Clinical Criteria for LATE Distinguish Cognitive Trajectories from Alzheimer Disease

The Diagnostic Challenge of TDP-43 in the Aging Brain

For decades, the clinical diagnosis of dementia in the oldest-old was largely synonymous with Alzheimer disease, yet autopsy studies have frequently revealed a distinct proteinopathy involving the transactive response DNA-binding protein of 43 kDa (TDP-43), a protein typically associated with amyotrophic lateral sclerosis that misfolds and aggregates in the aging brain [1]. This condition, now termed limbic-predominant age-related TDP-43 encephalopathy (LATE), often presents as an amnestic syndrome that is clinically indistinguishable from Alzheimer-type dementia [2, 3]. While Alzheimer disease is defined by amyloid-beta plaques and tau tangles, LATE involves a stereotypical progression of TDP-43 inclusions through the amygdala and hippocampus [1, 4]. In a longitudinal study of 3,606 memory clinic patients, those classified with Probable-LATE demonstrated slower cognitive decline on the Mini-Mental State Examination (p = 0.02) and a lower mortality risk (hazard ratio 0.70; 95% CI, 0.49 to 0.99) compared to those with Alzheimer disease [5]. However, the presence of comorbid LATE and Alzheimer pathology, which occurs in approximately 3.5% of symptomatic clinic patients, significantly accelerates decline in executive functioning (p = 0.03) and increases mortality (hazard ratio 1.25; 95% CI, 1.01 to 1.53) [5, 6, 7]. A recent study now evaluates how well clinical criteria can separate these distinct biological entities to improve longitudinal care and prognostic counseling for symptomatic patients.

Classifying the Amsterdam Memory Clinic Cohort

The researchers conducted a retrospective examination of a longitudinal memory clinic cohort from the Alzheimer Center Amsterdam to determine if clinical criteria could effectively differentiate between various neurodegenerative pathologies. This study included 3,606 individuals with mild cognitive impairment (MCI) or dementia who were over 50 years of age. The cohort had a mean age at baseline of 66 years (standard deviation 6), and 49.2% of the participants were female. To categorize these patients, the authors utilized an operationalization of clinical criteria that integrated baseline data on cognition, patterns of brain atrophy (the loss of neurons and their connections resulting in reduced brain volume), and biomarkers for amyloid-status and tau-status, which are the hallmark proteins used to define Alzheimer disease. This classification system allows clinicians to move beyond a binary Alzheimer diagnosis and consider the biological heterogeneity of cognitive decline.

Divergent Clinical Trajectories and Survival

Using this multidimensional approach, the study classified the participants into four distinct groups to compare their clinical trajectories. Of the total sample, 1,675 individuals (46.5%) were classified as having Alzheimer disease without evidence of limbic-predominant age-related TDP-43 encephalopathy (LATE). In contrast, the researchers identified that 8.2% of participants with MCI or dementia met the criteria for some form of LATE, a finding that suggests this pathology is a significant contributor to cognitive impairment in clinical settings. Specifically, 56 individuals (1.6%) were classified as Probable-LATE, while 115 individuals (3.2%) were categorized as Possible-LATE. Furthermore, 127 individuals (3.5%) were identified as having co-occurring LATE and Alzheimer disease, a group designated as LATE-AD. The longitudinal data revealed that patients classified as having Probable-LATE experienced a significantly slower rate of cognitive decline compared to those with Alzheimer disease across all measured domains. On the Mini-Mental State Examination (MMSE), a standard tool for assessing global cognitive impairment, the Probable-LATE group showed slower progression (standardized beta [sβ] = 0.12, standard error [SE] = 0.05, p = 0.02). This pattern of relative stability extended to specific cognitive functions, including memory (sβ = 0.11, SE = 0.5, p = 0.01), attention (sβ = 0.12, SE = 0.16, p = 0.05), and executive functioning (sβ = 0.09, SE = 0.04, p = 0.03). Even visuospatial functioning, which involves the ability to perceive and manipulate visual information, declined more slowly in the Probable-LATE group than in the Alzheimer disease group (sβ = 0.10, SE = 0.05, p = 0.05). Conversely, the presence of comorbid pathology in the LATE-AD group was associated with a more aggressive clinical course than Alzheimer disease alone. These patients exhibited a faster rate of decline on the MMSE (sβ = -0.12, SE = 0.05, p = 0.01). The acceleration of impairment was particularly evident in non-amnestic domains, with faster decline observed in attention (sβ = -0.13, SE = 0.06, p = 0.04) and executive functioning (sβ = -0.10, SE = 0.05, p = 0.03). These findings suggest that the accumulation of both amyloid-tau and TDP-43 proteins may have a synergistic effect on neurodegeneration, leading to a more rapid loss of cognitive capacity than either pathology in isolation. Survival analyses further distinguished these clinical phenotypes, providing critical prognostic information for clinicians. Compared to patients with Alzheimer disease, individuals with Probable-LATE had a 30 percent lower risk of mortality (hazard ratio [HR] 0.70, 95% CI 0.49 to 0.99, p = 0.04). In stark contrast, the mortality risk was 25 percent higher in the LATE-AD group compared to the Alzheimer disease group (HR 1.25, 95% CI 1.01 to 1.53, p = 0.04). These divergent outcomes emphasize that identifying the underlying proteinopathy is essential for accurate counseling regarding disease progression and life expectancy in the memory clinic setting.

Neuroimaging Markers of TDP-43 Pathology

Structural neuroimaging at baseline revealed distinct patterns of atrophy that help differentiate LATE from Alzheimer disease. The researchers utilized the inferior temporal-to-hippocampus ratio as a marker for limbic-predominant atrophy, a metric that compares the volume of the inferior temporal cortex to the hippocampus to identify localized neurodegeneration. Compared to patients with Alzheimer disease, those classified as Probable-LATE and Possible-LATE exhibited significantly higher ratios (sβ = 0.59, SE = 0.16, p < 0.01; sβ = 0.40, SE = 0.13, p < 0.01, respectively). This finding suggests that LATE pathology is characterized by a more concentrated degeneration within the limbic system, which is critical for memory formation, than the more widespread temporal lobe involvement typically observed in Alzheimer disease. Further analysis of subcortical structures showed that amygdalar volumes were consistently smaller across all LATE subgroups when compared to the Alzheimer disease group. Specifically, patients with Probable-LATE (sβ = -0.55, SE = 0.15, p < 0.01), Possible-LATE (sβ = -0.43, SE = 0.12, p < 0.01), and comorbid LATE-AD (sβ = -0.62, SE = 0.11, p < 0.01) all demonstrated reduced volume in the amygdala at baseline. For clinicians, this indicates that amygdalar atrophy may serve as a sensitive indicator of underlying TDP-43 pathology. Additionally, the study found that individuals with comorbid LATE-AD had a thinner cortex at baseline in an Alzheimer disease-signature composite region (a grouping of brain areas typically affected early in Alzheimer disease, such as the entorhinal and parahippocampal cortices) compared to those with Alzheimer disease alone (sβ = -0.73, SE = 0.11, p < 0.01). This increased cortical thinning likely reflects the additive burden of dual proteinopathies, correlating with the more rapid clinical decline observed in this subgroup. These findings underscore the value of clinical criteria in identifying individuals with suspected LATE, allowing for improved diagnostic and prognostic accuracy in the memory clinic.

References

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