Characterizing individuals fulfilling clinical criteria for LATE in a tertiary memory clinic

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is characterized by an amnestic-and limbic-predominant phenotype, which can mimic the clinical presentation of Alzheimer’s disease (AD). Differentiating between LATE and AD is imperative in the era of disease-modifying treatments for AD, but there are no established biomarkers to detect TDP-43. In this observational study, we characterized individuals fulfilling the recently proposed clinical criteria for LATE in a tertiary memory clinic setting in terms of cognition, atrophy, and disease course.

From the Amsterdam Dementia Cohort (ADC), we included 3606 individuals aged above 50 years old who had a diagnosis of MCI or dementia. We first classified individuals based on criteria for memory impairment, atrophy, amyloid-status and tau-status, into (Probable and Possible) LATE, co-occurring LATE and AD (Possible LATE-AD), and AD without LATE. Next, we compared these four groups on demographic, clinical, cognitive, and brain atrophy data. Longitudinal cognitive data were available for a subset.

We classified 56/3606 (1.6% of the total group) as Probable LATE, 115 (3.2%) as Possible LATE, 127 (3.5%) as Possible LATE-AD, and 1675 (46.5%) as AD. The remaining 1633 (45.3%) were not classified within this framework (e.g., frontotemporal dementia). At baseline, individuals with Probable LATE had lower memory scores but higher scores on all other domains and MMSE than AD, while individuals with Possible LATE-AD had worse scores across all cognitive scores than AD (p<0.05). Individuals with Probable LATE progressed slower than AD on MMSE (sβ[SE]=0.12[0.05], p=0.02), memory (sβ[SE]=0.24[0.1], p=0.01), attention (sβ[SE]=0.34[0.17], p=0.05), and executive functioning (sβ[SE]=0.19[0.09], p=0.03). Individuals with Possible LATE-AD progressed faster than AD on MMSE (sβ[SE]=-0.12[0.05], p=0.01), attention (sβ[SE]=-0.35[0.17], p=0.04), and executive functioning (sβ[SE]=-0.2[0.09], p=0.03). Mortality risk, compared to AD, was lower in individuals with Probable LATE (HR=0.70 [0.49-0.99], p=0.04) and higher in Possible LATE-AD (HR=1.25 [1.01-1.53], p=0.04). Compared to AD, at baseline, individuals with Probable and Possible LATE had higher inferior temporal-to-hippocampal ratios (indicating limbic-predominant atrophy; β[SE]=0.27[0.08], p<0.01; β[SE]=0.38[0.11], p<0.01), and Probable LATE additionally showed smaller amygdalar volumes (β[SE]=-2.36[0.75], p<0.01). Individuals with Possible LATE-AD had thinner cortex at baseline in an “AD-signature” composite region compared to AD (β[SE]=-2.14[0.64], p=0.01; β[SE]=-3.26[0.96], p<0.01).

Among individuals from a tertiary memory clinic (mean age: 66 [6]), 8.2% were classified as Possible LATE, Probable LATE, or Possible LATE-AD. Probable and Possible LATE were characterized by a milder disease course than AD, while LATE-AD was characterized by a more aggressive disease course. These differential clinical trajectories highlight the prognostic utility of clinically defining LATE in vivo .