A New Way to Stage Alzheimer’s Disease?

LOS ANGELES — A novel beta-amyloid (Aβ) staging system using PET imaging successfully tracked Alzheimer’s disease progression over time, a longitudinal study presented here showed.

“The staging system we defined is very robust and classified almost all participants unambiguously,” said Niklas Mattsson, MD, PhD, of Lund University in Malmo, Sweden, who presented the study at the 2019 Alzheimer’s Association International Conference (AAIC). “The stages also had longitudinal validity, meaning that people in lower stages were likely to progress to higher stages over time.”

The findings, which were also published simultaneously in JAMA Neurology, make it possible to identify and follow stages of amyloid deposition, Mattsson told MedPage Today. “This can be used both to improve research studies and perhaps also in clinical trials to learn, for example, if certain drugs are likely to be most effective in certain stages of Alzheimer’s disease.”

Clinical staging also can offer a framework to define a patient’s capabilities and provide predictive information about the disease course, noted Christian Camargo, MD, of the University of Miami Miller School of Medicine in Florida, who was not involved with the study.

“Notable about this new system is that Aβ PET stages are associated with cerebrospinal fluid biomarkers, clinical progression, and distinct gene expression patterns,” he told MedPage Today. “It presents a similar but distinct methodology to previously devised Aβ staging models,” such as one published in 2017 in Neurology, he added.

Staging offers significant potential for clinicians who treat Alzheimer’s patients, Camargo continued: “Further research applying these staging systems in clinical environments may further justify and expand the role of Aβ scans in clinical practice.”

To create their system, Mattsson and colleagues used data from the multi-site Alzheimer’s Disease Neuroimaging Initiative (ADNI) database of PET scans performed from June 2010 to July 2018 on 741 people: 304 people without cognitive impairment, 384 with mild cognitive impairment, and 53 with Alzheimer’s dementia. Participants were followed up at 2, 4, and 6 years and had cerebrospinal fluid (CSF) samples analyzed for the 42-residue form of Aβ (Aβ₄₂), total tau, and phosphorylated tau (p-tau).

The researchers used CSF Aβ₄₂ and ¹⁸F-florbetapir to determine early, intermediate, and late regions of Aβ accumulation. The early region included the precuneus, posterior cingulate, isthmus cingulate, insula, and medial and lateral orbitofrontal cortices. The late region included the lingual, pericalcarine, paracentral, precentral, and postcentral cortices, and the intermediate region included the remaining parts.

The investigators then used the composites to construct Aβ stages that ranged from 0 to 3, with each subsequent stage involving more advanced regions. They replicated and validated findings using the Swedish BioFINDER cohort and gene expression data from the Allen Human Brain Atlas.

“A key aspect was the integration of CSF Aβ₄₂ and ¹⁸F-florbetapir PET data to construct (but not apply) the system,” they wrote. “This integration built on previous observations that some participants have pathologic CSF Aβ42 concentrations without pathologic Aβ PET uptake, which is associated with a greater risk for future Aβ, and which may be used to identify Aβ starting regions.”

Each stage had different characteristics and was associated with clinical progression. Concentrations of Aβ₄₂ in CSF dropped in stage 1 and p-tau levels increased. CSF total tau increased in stage 2 and cognitive decline accelerated. Atrophy accelerated in stage 3. While clinical symptoms often appeared in stages 2 and 3, some people remained cognitively unimpaired even in stage 3.

At baseline, people in stage 0 had a 14.7% risk (95% CI 11.2%-18.1%) of progressing to a higher stage, mainly to stage 1. Those in stage 1 — which had relatively few people — had a 71.4% risk (95% CI 50.0%-90.9%) and people in stage 2 had a 53.1% risk (95% CI 42.2%-64.0%) of progression.

After about 6 years, almost everyone in stages 1 and 2 at baseline had progressed to stage 3. Reversal to a lower stage, an indicator of system instability, was rare at 0.9%. Strong differences in gene expression emerged in the stages, especially for genes related to voltage-gated ion channel activity.

The study had several limitations, the researchers noted. It requires further validation because the replication cohort had cross-sectional PET data only. In addition, the investigators used CSF Aβ₄₂ alone, rather than adjusting for CSF Aβ₄₀ which may have shown closer associations with amyloid PET.