Plasma Biomarker of Neurodegeneration Is Elevated in Colombian Kindred 22 Years Before Alzheimer's Symptoms
Key findings
- This study involved measurement of neurofilament light chain (NfL) in 2,144 members of the world's largest kindred in which autosomal dominant Alzheimer's disease is due to a single mutation
- Baseline plasma NfL concentration differed significantly between carriers and age-matched noncarriers (18 vs. 9 pg/mL, P < 0.0001)
- The annual increase in NfL was significantly higher in carriers than noncarriers (15 vs. 2 pg/mL; P = 0.008), and in carriers, the annual increase was highly correlated with the baseline concentration
- NfL concentration began to significantly differentiate carriers from noncarriers at age 22 (22 years before the median age of onset of mild cognitive impairment in this kindred)
- Greater NfL concentration was associated with poorer baseline performance on cognitive tests and greater annual decline in scores
Subscribe to the latest updates from Neuroscience Advances in Motion
Neurofilament light chain (NfL), a major component of large myelinated axons, is a promising biomarker of the progression of Alzheimer's disease (AD) and multiple other neurologic diseases. Cross-sectional and longitudinal studies in autosomal dominant AD have shown that NfL serum distinguishes mutation carriers from noncarriers years before the carriers' predicted age of symptom onset.
Yakeel T. Quiroz, PhD, director of the Familial Dementia Neuroimaging Lab and the Multicultural Alzheimer's Prevention Program at Massachusetts General Hospital, in collaboration Henrik Zetterberg, MD, PhD, and Kaj Blennow, MD, PhD, from the Sahlgrenska University Hospital, and Francisco Lopera, MD, from Universidad de Antioquia, and colleagues have extended previous findings: by studying a much larger number of individuals over an unprecedently wide age range and a homogeneous population where the average age of dementia onset is well established. In The Lancet Neurology, they report associations of NfL with baseline cognitive performance and subsequent decline.
Study Details
The researchers studied 2,144 adults and children, ages 8 to 75, who were enrolled in a registry of the PSEN1 E280A mutation kindred in Antioquia, Colombia. This is the world's largest kindred in which autosomal dominant AD is due to a single mutation. Carriers are known to develop mild cognitive impairment (MCI) at a median age of 44 and dementia at a median age of 49.
The participants included 1,070 mutation carriers and 1,074 noncarriers matched for age. None had any other medical conditions and they each contributed a blood sample for measurement of NfL in plasma.
Baseline NfL
At baseline, the average NfL concentration was higher in carriers than noncarriers (18 vs. 9 pg/mL, P < 0.0001).
1,470 adults among the 2,144 participants underwent clinical and cognitive assessments at baseline. In this subgroup, there were 573 unimpaired carriers, 154 impaired carriers and 743 noncarriers. The baseline NfL was significantly higher in impaired carriers than in age-matched noncarriers, and there was no significant difference between unimpaired carriers and noncarriers.
Longitudinal NfL Analysis
NfL concentration was remeasured annually over an average of six years (range, 1–13) in 262 carriers and 242 noncarriers. The annual increase in NfL was significantly higher in carriers than noncarriers (15 vs. 2 pg/mL; P = 0.008), and in carriers, the annual increase was highly correlated with baseline concentration.
Elevated cross-sectional NfL concentrations in carriers began to differ from noncarriers at an average age of 22 (22 years before the predicted onset of MCI at age 44). However, NfL concentrations were < 60% sensitive in predicting MCI until about three years before onset.
Correlations with Cognitive Tests
Higher plasma NfL concentrations were significantly associated with:
- Lower baseline total score on the Mini-Mental State Examination (MMSE) in impaired and unimpaired carriers
- Greater annual decline in MMSE score in all carriers
- Greater annual decline in word recall scores in carriers after adjustment for age
Clinical and Research Implications
Together with previous research, this study supports the use of NfL and other blood-based biomarkers to detect and track the preclinical and clinical stages of AD and related disorders.
NfL should also be helpful in clinical trials that evaluate risk modifiers for neurodegenerative diseases or investigate disease-modifying treatments. In fact, the researchers plan to study whether including NfL in the analysis of response could reduce the number of participants required and the trial duration.
view original journal article Subscription may be required
Learn more about the Multicultural Alzheimer's Prevention Program
Refer a patient to the Department of Neurology