# Biomarker‐Driven Patterns of Hippocampal Subfield Atrophy in Amnestic Mild Cognitive Impairment

## TL;DR

This study identifies distinct patterns of hippocampal atrophy in amnestic MCI based on amyloid and tau biomarker profiles, suggesting potential for early Alzheimer's detection.

## Contribution

The study reveals novel subfield-specific atrophy patterns linked to amyloid and tau biomarker profiles in early Alzheimer's disease.

## Key findings

- The A-T+ group showed faster atrophy in the subiculum bilaterally, indicating tau pathology's specific impact.
- The A+T+ group exhibited widespread atrophy across multiple hippocampal subfields, suggesting combined amyloid and tau pathology leads to broader degeneration.
- Subfield-specific atrophy patterns may serve as sensitive biomarkers for differentiating early Alzheimer's stages.

## Abstract

Hippocampal atrophy is a well‐established hallmark of Alzheimer's disease (AD), closely associated with cognitive decline and disease progression, even in the earliest symptomatic stages. Despite growing evidence that subfield‐specific atrophy patterns could serve as sensitive biomarkers for early diagnosis and tracking disease progression, there remains a significant gap in understanding how these subfields are differentially impacted across different stages of AD. In this study, we explore longitudinal rates of atrophy in hippocampal subfields in individuals with amnestic mild cognitive impairment (MCI).

Hippocampal subfields volumes were extracted from volumetric, T1‐weighted MRI images from the Alzheimer's Disease Neuroimaging Initiative using Freesurfer (v 7.4.1). We included individuals with MCI who underwent cerebrospinal fluid (CSF) collection and MRI studies at baseline and after 1 year. Participants were categorized according to baseline CSF levels of amyloid and phosphorylated‐tau proteins as: A‐T‐, A+T‐, A‐T+, and A+T+. Using generalized linear models, we evaluated the effect of biomarker subgroups on hippocampal subfield atrophy rates, controlling for age, sex, and whole hippocampal volume.

Table 1 summarizes demographic data for each biomarker group. Using the A‐T‐ group as reference, higher rates of atrophy were observed in the A‐T+ group in the subiculum, bilaterally. The A+T‐ group showed differences in the left presubiculum and in the subiculum, bilaterally. In the A+T+ group, faster atrophy was observed in the bilateral parasubiculum, bilateral subiculum, bilateral presubiculum, bilateral CA1, right CA4, and right dentate gyrus (granule cell and molecular layers) ‐ Figure 1.

This study reveals distinct patterns of hippocampal subfield atrophy in amnestic MCI, according to amyloid‐beta (A) and phosphorylated tau (T) biomarker profiles. The A‐T+ group exhibited a unique pattern of subfield vulnerability, primarily affecting the subiculum, suggesting that tau pathology alone may target specific regions of the hippocampus. In contrast, the A+T+ group showed widespread atrophy across multiple subfields, indicating that combined amyloid and tau pathology leads to more extensive hippocampal degeneration. These findings highlight the potential of subfield‐specific atrophy patterns as sensitive biomarkers for differentiating early AD stages and tracking disease progression. Future studies should investigate how these patterns correlate with cognitive decline and their predictive value for dementia conversion.