BACKGROUND

Progression of AD is associated with microstructural changes in the brain that often precede atrophy1

FW-DTI is an MRI technique that characterizes the diffusion of water molecules in tissue2 and can be used to measure microstructural changes in the brain3

Baseline diffusion scans were available from sub-studies of three late-phase, multicenter clinical trials in participants with early symptomatic AD with confirmed amyloid or tau pathology:
TRAILRUNNER-ALZ 1 (NCT05463731),4
TRAILBLAZER-ALZ 6 (NCT05738486),5,6
and PROSPECT-ALZ (NCT05063539)7,8

METHODS

Baseline diffusion scans from participants with available DTI data across three trials were analyzed

Extracellular FW and tissue-specific diffusion properties were modeled using FW-DTI; measures by brain region are summarized in Table 1 and Figure 1

Table 1: Measures Used in Different Brain Regions

Figure 1: Variables Investigated

RESULTS

Table 2: Key Baseline Characteristics and Biomarker Eligibility of Participants Analyzed Across Three Clinical Trials

Figure 2: FW, MDT, and FAT in Gray and White Mattera Were Higher in PROSPECT-ALZ Compared to Other Late-Phase Clinical Trials in Early Symptomatic AD

PROSPECT-ALZ had a higher proportion of APOE ε4 carriers (Table 2) among similar age ranges, suggesting that confirming eligibility by P-tau217 and tau PET positivity versus amyloid PET positivity may enrich for APOE ε4 carriers

Least squares mean and 95% CI (adjusted for APOE ε4 carrier status and MMSE score) of each FW-DTI measure across clinical trials are shown in Figure 2

FW and MDT estimates were numerically higher in the hippocampus versus cortex, consistent with the typical spatial spread of AD pathology

Hippocampal and white-matter FW and hippocampal MDT were not significantly different between trials requiring only amyloid presence (TRAILRUNNER-ALZ 1 and TRAILBLAZER-ALZ 6) but were higher in PROSPECT-ALZ, which required tau positivity

The pairwise differences in magnitude were larger (10× greater cortical MDT, 2× greater white-matter FAT) for PROSPECT-ALZ versus other trials than for TRAILBLAZER-ALZ 6 versus TRAILRUNNER-ALZ 1

CONCLUSION