Clinical Manifestations

Patients with memory concerns but negative Positron Emission Tomography (PET) amyloid scans pose significant diagnostic challenges, requiring differentiation between non-Alzheimer's disease (AD) pathologies. Limbic-predominant Age-related TDP-43 Encephalopathy (LATE) has emerged as a notable alternative diagnosis, characterized by impaired delayed recall, preserved verbal fluency, and medial temporal atrophy¹². Understanding the cognitive and MRI features that distinguish amyloid-negative from amyloid-positive patients is essential for refining diagnostic accuracy METHOD: This descriptive study included 56 patients with cognitive complaint (28 amyloid-PET- negative, 28 amyloid -PET-positive) who were evaluated between 2023 and 2025 at the UHN Memory Clinic and had a positron emission tomography (PET), MRI and Toronto Cognitive Assessment (ToRCA). Demographic, cognitive, amyloid PET scan and MRI data were compared, with medians and interquartile ranges (IQR) reported for non-normally distributed variables.

Both groups had similar age (70.0 [65.5-76.8] vs. 74.5 [66.0-78.0], p = 0.768) and sex distribution (57.1% male, p = 1.000). Amnestic MCI was more frequent in the amyloid-negative group (89.3% vs. 57.1%, p = 0.016), while dementia was more common in the amyloid-positive group. Amyloid-negative patients showed better delayed recall (3.00 [2.75-5.00] vs. 1.00 [0.00-3.25], p = 0.008), delayed recognition (19.00 [16.00-20.00] vs. 17.00 [12.00-18.00], p = 0.006), and visuospatial memory (Benson Figure Delayed Recall: 10.00 [8.00-12.00] vs. 8.00 [3.00-10.25], p = 0.021) than the amyloid-positive group. Semantic fluency (animals) was also higher (16.00 [12.00-18.25] vs. 13.00 [7.75-15.25], p = 0.006) in the amyloid-negative patients, while lexical fluency (F words) was comparable (p = 0.134). There were no significant differences in global cortical atrophy or moderate-to-severe atrophy of the medial temporal lobes.

This descriptive study suggests that amyloid-negative patients are more likely to present with aMCI than dementia, and exhibit milder memory deficits than amyloid-positive patients, aligning with reports that LATE may be less severe than AD. Though referral bias may partly explain the higher proportion of aMCI in the amyloid-negative group, these findings underscore the need to consider non-AD pathologies in patients with memory complaints and negative amyloid scans. Future research may elucidate distinct clinical signatures to improve diagnostic workflows in memory clinics.