Adults with Down syndrome (DS) have an increased risk of developing age-related Alzheimer’s Disease-like neurodegeneration during their lifetime. The prodromal stage of Alzheimer’s Disease (AD), before any apparent cognitive decline, is difficult to characterise in DS due to diagnostic overshadowing, where comorbidities are misdiagnosed or de-emphasised and attributed to DS, instead of AD. Current biomarkers are insufficient in capturing AD-related neuropathological changes early in the disease process, making the development of more sensitive AD biomarkers a priority in the fight against AD in DS.

As individuals age, declines in sensory function can profoundly impact cognitive abilities, particularly memory and attention. In typically developing (TD) individuals, the P50 event-related potential serves as a marker of amyloid-related neurophysiology. Contrary to patterns in TD individuals, in Down syndrome (DS), the frontal cortex is more vulnerable to neuropathology than the temporal cortex. The coordination of these two brain regions is integral to sensory gating (SG), and is reflected in the P50 ERP, elicited in a paired-click paradigm. Therefore, the P50 paired-click paradigm offers promise in detecting prodromal Alzheimer's in DS by capturing neurophysiological abnormalities, addressing the challenge of distinguishing intellectual disability-related cognition from AD-related cognition.

This thesis is the first to investigate the potential of the P50 as an early biomarker of neurophysiological changes and cognitive decline in DS. This work yielded five outcome variables: with the P50 ratio as the primary measure, and secondary measures comprised of latencies and amplitudes, elicited by neural generators in the temporal and frontal regions.

After adaptation, operationalisation, validation, and optimisation for use in DS, SG function, reflected in the P50 ratio, was found to be disrupted. Next, a longitudinal analysis of two cross-sectional studies showed that SG declined after six years. Additionally, for the DS group, there were investigations into the relationships between SG and (i) age, (ii) cognitive performance, (iii) diagnosis of dementia, and (iv) the presence of Aβ binding in the brain.

As hypothesised, the P50 ERP indicated abnormal cortical activity in adults with DS, compared to TD controls. Hyperexcitability of cortical responses predicted poor cognitive performance and amyloid deposition in the striatum. Amyloid build-up in the striatum predicted poorer SG two years later. This investigation provides evidence of a deficit in the brain’s ability to suppress activity at the fundamental electrical level, potentially causing cognitive and behavioural impairments typical of DS. The disruption of neurophysiological mechanisms, reflected in SG deficits, may indicate a lower degree of neural activity or less consistency in time-locked neural activity to an acoustic stimulus, which is likely to be a proxy for upstream cognitive function and signal susceptibility to AD. This electrophysiological signature, the P50 ERP, has the potential to be a biomarker of prodromal AD in DS.