A specific pattern of brain atrophy visible on MRI may help predict how quickly patients with early-onset Alzheimer’s disease (EOAD) progress from mild cognitive impairment (MCI) to dementia.

In a longitudinal study of patients with EOAD, greater baseline atrophy within vulnerable brain regions was associated with faster progression to dementia and provided prognostic information beyond baseline clinical severity — information that could ultimately help clinicians and families anticipate disease trajectory and plan care.

“The EOAD signature can complement clinical judgement by providing information on the extent of neurodegeneration, which is not captured by clinical severity measures alone,” study investigator Alexandra Touroutoglou, PhD, with the Mass General Brigham Neuroscience Institute in Boston, told Medscape Medical News.

“Indeed, when we added EOAD-signature atrophy to our model that already included clinical severity, we significantly improved the model’s ability to predict progression to dementia,” she added.

The study was published online on August 26 in Neurology.

A Prognostic MRI Marker

EOAD is defined by clinical onset before the age of 65. Although progression is faster on average than in later-onset AD, the pace varies substantially among patients, and clinicians lack sensitive tools to anticipate when functional independence will be lost.

“One of the most frequent questions patients ask at the clinic is, ‘When will I lose my independence?’ The uncertainty about what will happen next is one of the most difficult aspects of living with MCI due to EOAD,” said Touroutoglou.

Patients who appear relatively similar clinically may follow markedly different trajectories, with some remaining relatively stable, and others progressing more rapidly to dementia, she explained.

In earlier work, her team developed the EOAD MRI signature in a sample of patients with sporadic EOAD at the MCI or mild dementia stage. The signature captures cortical thinning across regions particularly vulnerable to EOAD.

This biomarker was strongly correlated with the magnitude of cognitive and functional impairment at baseline, but whether it could predict subsequent progression to dementia was unknown.

To investigate, the researchers studied 130 adults (mean age, 59.6 years; 49% women) with biomarker-supported sporadic EOAD at the MCI stage, defined by a global Clinical Dementia Rating (CDR) score of 0.5 at baseline.

MRI measures were referenced against 97 cognitively normal, age-matched participants from the LEADS cohort.

Greater Atrophy, Faster Progression

During a mean follow-up of roughly 2 years, 84 of 130 patients (65%) with MCI due to EOAD progressed to dementia. Those who progressed had greater cognitive impairment at baseline, reflected by higher CDR Sum of Boxes scores and lower Mini-Mental State Examination scores.

Greater baseline cortical atrophy within the EOAD signature was significantly associated with more rapid progression to dementia. For every 1-SD increase in the magnitude of atrophy, the risk for progression from MCI to dementia was 24% higher (hazard ratio, 1.24; P < .002).

Adding EOAD-signature atrophy to a model that included age, sex, and baseline cognitive-functional severity significantly improved model fit, suggesting that the MRI measure provides prognostic information beyond patients’ clinical status alone.

“Our results do not suggest that the MRI signature should replace clinical assessments,” said Touroutoglou. She emphasized that the MRI signature provided incremental prognostic information and should complement, rather than replace, clinical evaluation.

Better prognostic information could help patients and families plan for the future, guide clinical monitoring, and help identify the optimal window for therapeutic intervention, Touroutoglou said.

However, she added, the MRI signature is not ready for routine clinical use yet. The model was developed and evaluated within a single cohort that was predominantly non-Hispanic White, limiting its generalizability to more diverse populations.

An Important First Step

Most patients also had amnestic MCI, making it unclear whether the signature will perform similarly across other EOAD phenotypes, including behavioral, visuospatial, or language presentations.

“Our study is an important step toward a more personalized prognostication in EOAD but there is still work to do before the EOAD signature can be used in clinical care,” Touroutoglou said.

External validation in patients from more diverse racial, ethnic, and geographic backgrounds and testing across different clinical EOAD phenotypes are key next steps, she added.

The researchers also plan to explore multimodal approaches combining the EOAD MRI signature with clinical measures and other AD biomarkers, including blood- and PET-based measures.

Touroutoglou cautioned that no single biomarker can provide all the answers and that the MRI signature should be considered alongside other clinical information.

Practical barriers also remain. Although the signature is derived from standard structural MRI routinely obtained during diagnostic assessment, calculating it requires image processing that is not currently part of clinical practice. Automated, standardized, and user-friendly tools will be needed before the approach can be widely adopted, she said.

This study was supported by the National Institutes on Health and the Alzheimer’s Association. The authors had no relevant disclosures.