Date Published: April 10, 2018
Publisher: BioMed Central
Author(s): Andre Strydom, Amanda Heslegrave, Carla M. Startin, Kin Y. Mok, John Hardy, Jurgen Groet, Dean Nizetic, Henrik Zetterberg.
Down syndrome (DS) may be considered a genetic form of Alzheimer’s disease (AD) due to universal development of AD neuropathology, but diagnosis and treatment trials are hampered by a lack of reliable blood biomarkers. A potential biomarker is neurofilament light (NF-L), due to its association with axonal damage in neurodegenerative conditions.
We measured blood NF-L concentrations in 100 adults with DS using Simoa NF-light® assays, and we examined relationships with age as well as cross-sectional and longitudinal dementia diagnosis.
NF-L concentrations increased with age (Spearman’s rho = 0.789, p < 0.001), with a steep increase after age 40, and they were predictive of dementia status (p = 0.022 adjusting for age, sex, and APOE4), but they showed no relationship with long-standing epilepsy or premorbid ability. Baseline NF-L concentrations were associated with longitudinal dementia status. NF-L is a biomarker for neurodegeneration in DS with potential for use in future clinical trials to prevent or delay dementia.
Down syndrome (DS), caused by the trisomy, translocation, or partial trisomy of chromosome 21, is the most common genetic cause of intellectual disability (ID), with an estimated population prevalence of 6 million worldwide. Dementia is a common feature of the aging process in DS that is due to the triplication of the amyloid precursor protein on chromosome 21, leading to brain pathology indicative of Alzheimer’s disease (AD) , with a cumulative incidence for dementia in excess of 90% by the age of 65  and a mean age at dementia diagnosis of 55 . DS is therefore a genetic form of AD alongside autosomal dominant causes of AD .
Participants aged 16 years and older were recruited across England via care homes, support groups, and local NHS sites. Participants with an acute physical or mental health condition were excluded until they had recovered; other details of the cohort have been described previously . DS status was confirmed using DNA from saliva or blood and genotyped using OmniExpressExome arrays (Illumina, San Diego, CA, USA); trisomy status was visually confirmed in GenomeStudio software (Illumina) (see Table 1). Apolipoprotein E (APOE) status was determined using TaqMan assays for rs7412 and rs429358 (Thermo Fisher Scientific, Waltham, MA, USA).Table 1Demographics of all participants included in group and subgroup analysesAll participantsDementia (baseline)No dementia (baseline)Participants with follow-up dataNumber of subjects94187629Age at baseline, years, mean ± SD (range)42.68 ± 14.87 (17–73)55.17 ± 9.92 (40–69)39.72 ± 14.34 (17–73)52.63 ± 8.88 (40–72)DS type89 (94.7%) trisomy, 2 (2.1%) translocation, 3 (3.2%) unknown18 (100.0%) trisomy71 (93.4%) trisomy, 2 (2.6%) translocation, 3 (3.9%) unknown28 (96.6%) trisomy, 1 (3.4%) unknownSex41 (43.6%) female, 53 (56.4%) male6 (33.3%) female, 12 (66.7%) male35 (46.1%) female, 41 (55.9%) male10 (34.5%) female, 19 (65.5%) maleEthnicity85 (90.4%) white, 9 (9.6%) other17 (94.4.0%) white, 1 (5.6%) other68 (89.5%) white, 8 (10.5%) other27 (93.1%) white, 2 (6.8%) otherPredementia ID level37 (39.4%) mild, 47 (50%) moderate, 9 (9.6%) severe, 1 (1.2%) unknown6 (33.3%) mild, 9 (50.0%) moderate, 3 (16.7%) severe31 (40.8%) mild, 38 (50%) moderate, 6 (7.9%) severe, 1 (1.3%) unknown13 (44.8%) mild, 12 (41.4%) moderate, 3 (10.3%) severe, 1 (3.4%) unknownAPOE status68 (72.3%) non-APOE4 carrier, 23 (24.5%) APOE4 carrier, 3 (3.2%) unknown12 (66.7%) non-APOE4 carrier, 5 (27.8%) APOE4 carrier, 1 (5.5%) unknown56 (73.7%) non-APOE4 carrier, 18 (23.7%) APOE4 carrier, 2 (2.6%) unknown22 (75.9%) non-APOE4 carriers, 6 (20.7%) APOE4 carrier, 1 (3.4%) unknownNF-L level, ng/L, median (range)22.74 (6.11–136.91)63.76 (15.21–136.91)19.96 (6.11–116.84)32.67 (12.23–481.97)Abbreviations: DS Down syndrome, ID Intellectual disability, APOE Apolipoprotein E, APOE4, Apolipoprotein E E4 allele, NF-L Neurofilament light
NF-L levels were obtained from 100 participants (age range 17–73 years). Five results were excluded after failing to meet CV thresholds, meaning 95 adults were included in subsequent analyses. Of adults aged 36 and older who are being targeted for longitudinal follow-up, 29 of 63 (46%) had completed a follow-up assessment at the time of this report (mean number of months between assessments 23.4, SD 3.9). One individual had experienced an occlusive cerebrovascular event 4–6 months prior to donating the blood sample and converted to dementia status at follow-up but was an outlier with an NF-L level of 481.97 ng/L; thus, this individual was excluded from cross-sectional analysis. Among the remaining 94 individuals, NF-L concentration had a median value of 22.74 ng/L (range 6.11–136.91 ng/L). At baseline, 18 of 94 participants had a clinical diagnosis of dementia (Table 1).
We have demonstrated that NF-L measured in blood using an ultrasensitive assay is strongly associated with age and dementia status in individuals with DS, and baseline levels were predictive of dementia diagnosis over time. Furthermore, NF-L levels did not differ according to severity of premorbid ID or by long-standing epilepsy diagnosis (a common neurological comorbidity in DS), suggesting that it is a stable and feasible biomarker that can be used in clinical populations.
Although further work is required to establish long-term predictive and concurrent validity of NF-L, our data suggest that this biomarker could be instrumental in allowing an experimental medicine approach in individuals with DS and other high-risk populations to test treatments that might prevent or delay dementia onset.