Differential CSF Biomarkers in Autosomal Dominant AD and Down Syndrome

Alzheimers disease. Computer illustration of a healthy neuron (left), a neuron with amyloid plaques (yellow, centre), and a dead neuron being digested by microglia cells (red, right).
A team of investigators conducted a cross-sectional study to compare CSF biomarker patterns in Down syndrome compared with those of autosomal dominant Alzheimer disease mutation carriers.

In a cross-sectional study of Alzheimer disease (AD) among individuals with Down syndrome, study researchers observed significant differences in amyloid b (Ab) and chitinase-3-line protein 1 (YKL-40) levels compared with patients with AD. These findings were published in Lancet Neurology.

The Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS) study recruited patients with Down syndrome and autosomal dominant AD mutations between 2015 and 2018. Study researchers assessed participants for cerebrospinal fluid (CSF) biomarkers and compared results with data collected between 2009 and 2018 for the Dominantly Inherited Alzheimer Network (DIAN) study which comprised individuals who were AD mutation carriers and their noncarrier siblings.

Participants with Down syndrome (n=41) included 26 men and 15 women, and the DIAN study participants (n=300) included 137 men and 163 women who were dominant mutant carriers (n=192) and their noncarrier siblings (n=108).

The 3 cohorts differed significantly for age, cognitive status, and all CSF biomarkers (all P <.001).

Compared with the noncarrier siblings, the Down syndrome cohort differed significantly for CSF biomarkers total tau, p-tau181, Ab1-42:Ab1-40 ratio, and visinin-like protein 1 (VILIP-1; all P <.008). Compared with the AD carriers, the Down syndrome cohort differed significantly for Ab1-42 (P <.0008). Compared with either groups, the Down syndrome individuals differed significantly for Ab1-40, total tau:Ab1-42, p-tau181:Ab1-42, and YKL-40.

Dementia was symptomatic among 34% of the Down syndrome and 43% of the AD mutation carriers. Among the symptomatic individuals with Down syndrome, levels of Ab1-40 differed significantly (P =.040). Among all symptomatic individuals, Ab1-42 was significantly lower (P £.001) and YKL-40 was significantly higher (P £.010).

The study investigators modeled the progression of AD as a function of age. The age-related biomarker patterns were similar among both the Down syndrome and mutation carrier cohorts; even fewer markers in Down syndrome cohort differed significantly from the noncarriers. However, those with Down syndrome had higher Ab1-40 and greater YKL-40 slopes than either cohort and they did not differ from the noncarriers for the slope of total tau or tau:Ab1-42.

This study was limited by power due to the low number of samples from individuals with Down syndrome.

These data indicated that CSF biomarker patterns among individuals with Down syndrome who were carriers of AD mutations exhibited many similar patterns as individuals with AD, except that Down syndrome associated with differing Ab and YKL-40 trajectories.

Disclosure: Multiple authors declared affiliations with the pharmaceutical industry. Please refer to the original article for a full list of disclosures.


Fagan AM, Henson RL, Li Y, et al. Comparison of CSF biomarkers in Down syndrome and autosomal dominant Alzheimer’s disease: a cross-sectional study. Lancet Neurol. 2021;20(8):615-626. doi:10.1016/S1474-4422(21)00139-3