A blood test that detects changes in levels of a protein in the blood may predict the development of familial early-onset Alzheimer's disease up to 16 years before clinical symptoms start to appear.
These are the results of a study published online in Nature Medicine on January 21.
In Alzheimer's disease, brain changes such as cortical thinning and amyloid-beta and tau deposits develop years before clinical symptoms. Magnetic resonance imaging (MRI) and positron-emission tomography (PET) scans and a lumbar puncture to measure levels of amyloid-beta and tau protein in the cerebrospinal fluid (CSF) are used to assess these changes. But a lumbar puncture is invasive and imaging techniques are expensive, making them impractical for routine clinical practice.
Recently, investigators have been looking at neurofilament light chain (NfL), a protein in brain cells that is part of the cells’ internal skeleton, as a potential biomarker for neurodegenerative diseases such as Alzheimer's. Damaged and dying neurons release NfL into the CSF, where it then travels into the bloodstream. Researchers hypothesize that detecting NfL levels in the blood can be used identify patients who will go on to develop clinical symptoms of Alzheimer’s.
To determine whether NfL levels in the blood and CSF correlate with one another and are elevated before clinical symptoms appear, an international team of researchers analyzed 405 participants in the Dominantly Inherited Alzheimer Network (DIAN), a study examining the causes of Alzheimer's disease.
Participants in this study have rare genetic mutations, such as APP, PSEN1, PSEN2, known to cause dominantly inherited Alzheimer's disease (DIAD), an early-onset form. Typically, these patients experience memory loss and other symptoms of dementia in their thirties, forties, and fifties.
The researchers analyzed 243 participants with a mutation and 162 family members without it. Participants in the DIAN study attended a DIAN clinic, gave blood samples, underwent CSF tests, completed cognition tests of memory and thinking skills, and had a series of brain scans. The group was assessed at the start of the study and at subsequent follow-up visits, once every three years, for six to nine years.
Patients with a mutation showed significantly increased NfL blood levels, which also correlated with CSF levels, as both were elevated before the anticipated start of clinical symptoms.
In comparison, family members with no mutation had low NfL levels that remained steady throughout the study.
In those with a genetic mutation, NfL levels increased over time, with the rate of change closely associated with cortical thinning (a deterioration of cognitive functions, such as perception, language, memory, and consciousness) as seen on an MRI, but less closely associated with amyloid-beta deposits, as assessed by PET.
Differences in NfL levels were noticeable in the blood as early as 16 years before clinical symptoms were expected to appear.
The rise of NfL levels was steepest in the years before symptom onset, before it levelled off as the symptoms emerged.
NfL bloods also predicted memory decline and thinking skills in the cognition tests.
The findings suggest blood tests could potentially detect Alzheimer's decades before the clinical symptoms begin to show.
"While an increase of NfL levels is not specific for Alzheimer’s disease, the present findings are relevant for understanding Alzheimer’s disease progression. They also highlight their utility as a marker in clinical trials," the researchers wrote. Regularly measuring NfL in the blood could be a reliable, affordable, and quick assessment of neurodegeneration in the brain, the researchers said.
Further investigation is needed to determine the exact amount of NfL in the blood that can predict the rate of disease progression.
