# Proteomics reveals three molecular subtypes of Alzheimer's disease with distinct progression patterns

## TL;DR

This study identifies three distinct molecular subtypes of Alzheimer's disease based on proteomics data, each with unique progression patterns and biological features.

## Contribution

The study introduces three biologically distinct Alzheimer's subtypes linked to specific molecular pathways and clinical outcomes.

## Key findings

- Three AD subtypes were identified with distinct molecular pathways and progression rates.
- Subtype 1 showed RNA metabolism dysregulation and slow progression.
- Subtype 3 was associated with catabolic processes and rapid neurodegeneration.

## Abstract

Alzheimer's disease (AD) shows marked molecular heterogeneity. Defining biological subtypes may refine diagnosis and treatment.

We analyzed cerebrospinal fluid (CSF) proteomics and longitudinal data from 550 participants in the Alzheimer's Disease Neuroimaging Initiative with up to 16.5 years of follow‐up. We profiled 6361 proteins, applied machine learning to identify biological subtypes, and validated them in three independent cohorts.

Three AD subtypes were identified. Subtype 1, enriched in RNA metabolism pathways, showed the mildest atrophy and slowest cognitive decline. Subtype 2, characterized by axonogenesis‐related pathways, exhibited the greatest CSF tau elevations, moderate atrophy, and intermediate decline. Subtype 3, associated with catabolic processes, showed the most severe atrophy and fastest progression. These patterns were consistently replicated across validation cohorts.

These findings demonstrate robust, biologically distinct AD subtypes linked to divergent molecular pathways, clinical features, and progression rates. Such refined stratification supports precision diagnostics and targeted therapeutic strategies.

Large‐scale CSF proteomics and machine learning identified three robust biological subtypes of AD.Subtypes exhibit distinct molecular processes accompanied by divergent cognitive trajectories, brain atrophy patterns, and progression rates.Subtype 1 showed RNA metabolism dysregulation with relatively stable disease course; subtype 2 was enriched in axonogenesis pathways with intermediate progression; subtype 3 was driven by catabolic processes with rapid neurodegeneration.

Large‐scale CSF proteomics and machine learning identified three robust biological subtypes of AD.

Subtypes exhibit distinct molecular processes accompanied by divergent cognitive trajectories, brain atrophy patterns, and progression rates.

Subtype 1 showed RNA metabolism dysregulation with relatively stable disease course; subtype 2 was enriched in axonogenesis pathways with intermediate progression; subtype 3 was driven by catabolic processes with rapid neurodegeneration.