Developing Topics.

Background: Due to the lack of in vivo molecular biomarkers for Limbic-predominant age-related TDP-43 encephalopathy (LATE), which commonly co-occurs with Alzheimer's disease (AD), it is challenging to identify patients with mixed AD/LATE pathology. Autopsy studies have suggested that AD patients with greater hippocampal atrophy are disproportionately enriched in having concomitant LATE. Here we define the lower quartile of hippocampal volume as a biomarker of possible LATE with AD.

Method: We identified 164 cognitively impaired participants from ADNI who had structural MRI, amyloid-PET, and tau-PET within 365 days. Patients were grouped based on hippocampal volume quartiles (adjusted for age and intracranial volume) and amyloid-PET-status into suspected 1) AD-only (volume>50th-percentile, amyloid-positive), n = 100, 2) LATE-only (volume<25th-percentile, amyloid-negative), n = 14, 3) AD+LATE (volume<25th-percentile, amyloid-positive), n = 50. 250 cognitively normal, amyloid-negative participants were also included. Patterns of atrophy were examined to assess whether the AD+LATE group had features suggestive of LATE beyond hippocampal atrophy.

Result: Suspected-AD+LATE group had lower MMSE, CDR, and hippocampal volume and higher ITG-tau-SUVR compared to the suspected-AD-only group (Figure-1A). Suspected-AD-only group showed predominant posterior hippocampal atrophy whereas LATE showed a more severe anterior hippocampal atrophy (Figure-1B/2B). When compared to the AD-only group, suspected LATE-only and AD+LATE groups showed significantly lower thickness in ERC, PHC, BA35, BA36 (Figure-2A); there were no differences between LATE-only and AD+LATE groups. Suspected-AD+LATE group showed features suggestive of LATE in prior work (Figure-2B). Whole brain analysis demonstrated that in comparison to controls the suspected-AD-only group showed lower thickness in typical AD regions (posterior hippocampus and temporoparietal regions), suspected-LATE-only group showed lower thickness in more anterior MTL regions including temporal pole consistent with LATE pathology, whereas suspected-AD+LATE group showed lower thickness in both AD- and LATE-like regions (Figure-3A). Assessing neurodegeneration driven due to non-tau factors by controlling for ITG-tau-SUVR revealed similar atrophy patterns for both suspected LATE-only and AD+LATE groups compared to the AD-only group. Both groups showed decreased thickness isolated to anterior hippocampus extending into temporal pole (Figure-3B).

Conclusion: Using a simple hippocampal volume percentile-based metric may enrich in patients with concomitant LATE on the AD continuum and could potentially be examined in the context of clinical trials and anti-amyloid therapies.