*6.2. Down's Syndrome*

DS is a high-risk factor for the early development of AD. Cognitive impairment in adults with DS resembles that of AD patients [229]. As observed in AD, adults with DS present greater brain MI levels, increasing with age [156]. This may be due to an extra copy of the SMIT1 gene in chromosome 21 [230]. Moreover, the overexpression of amyloid precursor APP due to its presence on chromosome 21 is likely the cause for the increased production of Aβ fragments [231]. Brain insulin resistance is also observed to be developed early in DS subjects, as seen in the inhibition of IRS1 and the uncoupling of downstream elements of insulin signaling [232,233]. These alterations are a major factor for triggering early AD in DS.

Given the prevalence of AD in DS, SI (ELND005) has been tested in a phase II clinical trial in subjects with DS. Both doses of 250 mg/day and 250 mg/twice a day of SI resulted in no serious adverse events, and increased SI concentration in plasma. Interestingly, although a small sample group was tested, the subjects with double dose of 250 mg SI showed improvements in their "neuropsychiatric inventory", a behavioral measure that assesses symptoms like irritability and agitation [234]. A phase III clinical trial with SI in DS is expected to start.
