Magnetic Resonance Imaging and Cerebrospinal Fluid Biomarker Clustering Defines Biological Subtypes of Alzheimer’s Disease

TL;DR

This study identifies three biological subtypes of Alzheimer’s disease using MRI and cerebrospinal fluid biomarkers, revealing distinct patterns of brain atrophy and pathology.

Contribution

The study introduces MRI-based clustering validated by CSF biomarkers to define biologically distinct Alzheimer’s subtypes.

Findings

Three AD subtypes were identified based on MRI and CSF data, including a tau/vascular limbic subtype and a volume-preserved low-amyloid subtype.

Progressive biological shifts from amyloid accumulation to tau aggregation and vascular compromise were observed across subtypes.

Multimodal phenotyping is suggested as a practical approach for precision staging and intervention in Alzheimer’s.

Abstract

Background/Objectives: Alzheimer’s disease (AD) exhibits clinical and biological variability. This study aimed to identify MRI-defined subtypes reflecting distinct biological pathways of neurodegeneration and cognitive decline. Methods: We applied principal component analysis followed by k-means clustering (k = 3) on volumetric MRI data from 924 participants and validated clusters using cerebrospinal fluid (CSF) biomarkers (Aβ42, total tau, p-tau, CTRED, MAPres, glucose, CTWHITE). Results: Three major phenotypes emerged: (1) a tau/vascular limbic subtype with pronounced hippocampal and amygdala atrophy and elevated tau and CTRED levels; (2) a volume-preserved, low-amyloid subtype consistent with early-stage or cognitively resilient AD; and (3) a diffuse-atrophy subtype with high amyloid and tau burden and ventriculomegaly. Comparative analysis revealed progressive biological shifts from amyloid accumulation to tau aggregation and vascular compromise across these clusters. Conclusions: MRI-based clustering validated by CSF biomarkers delineates biologically meaningful AD endophenotypes. The results suggest a gradual cognitive decline driven by amyloid–tau–vascular interactions, supporting multimodal phenotyping as a practical approach for precision staging and intervention.

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