# Detecting limbic predominant neurodegenerative co-pathologies in vivo in Alzheimer’s disease: magnetic resonance imaging markers, cognitive correlates, and prognosis

## TL;DR

This study identifies MRI markers to detect non-AD co-pathologies in Alzheimer's disease, linking them to memory impairment and faster disease progression.

## Contribution

The study introduces MRI-based biomarkers to distinguish Alzheimer's disease with co-pathologies from pure Alzheimer's.

## Key findings

- AD+ pathology is associated with greater hippocampal atrophy and less cortical degeneration compared to pure AD.
- AD+-classified atrophy in MCI is linked to faster clinical decline and more severe memory impairment.
- Cortical degeneration is a stronger predictor of clinical progression than hippocampal atrophy in mild dementia.

## Abstract

In Alzheimer’s disease (AD), limbic non-AD co-pathologies are common and contribute to memory impairment and accelerated clinical progression. To date, in vivo biomarkers of these co-pathologies are lacking. Here, we examined whether specific regional gray matter (GM) atrophy patterns on magnetic resonance imaging (MRI) allow distinguishing between patients with ‘pure’ AD pathology and those with AD pathology and limbic non-AD co-pathologies (AD+).

Atrophy patterns based on ante-mortem MRI scans of histopathologically confirmed ‘pure’ AD (n = 36) and AD+, i.e., AD pathology with concomitant limbic TDP-43 pathology and argyrophilic grain disease (n = 39), were applied to classify an independent cohort of clinically diagnosed patients with mild cognitive impairment (MCI, n = 224) and dementia (n = 221). Furthermore, we examined the degree to which an MRI marker of cortical degeneration reflecting tau pathology could improve the estimation of clinical progression.

Histopathologically confirmed AD+ pathology was associated with more substantial hippocampal atrophy but less cortical degeneration in intermediate Braak stage regions than ‘pure’ AD pathology. Clinically diagnosed AD patients with an AD+-classified ratio of cortical-to-hippocampal GM exhibited significantly more memory impairment. At the stage of MCI, AD+-classified atrophy was also associated with speeded clinical decline. Furthermore, tau-associated cortical degeneration emerged as the primary predictor of clinical progression across groups and disease stages.

The data suggest that in MCI due to AD, additional non-AD limbic co-pathologies are associated with greater hippocampal but less cortical atrophy and more rapid clinical decline. In contrast, in mild dementia due to AD, hippocampal GM was not associated with prognosis. Instead, cortical degeneration appeared to drive clinical progression.