UC Irvine

Virtually all people with Down syndrome (DS) will develop Alzheimer’s disease (AD). Most will also develop dementia, which is characterized by memory loss and functional impairment. The presence of a third copy of chromosome 21 appears to cause accelerated accumulation of the two hallmark pathologies of AD: β-amyloid (Aβ) plaques and neurofibrillary tangles of tau protein. Aβ plaques deposit early in regions of the brain that comprise the default mode network (DMN), while tau tangle deposition begins in the medial temporal lobe (MTL) and eventually spreads to the cortex. Widespread neurodegeneration and the onset of mild cognitive impairment (MCI) and dementia follow soon thereafter. This timeline of functional and structural brain changes relative to pathology accumulation and clinical symptoms is generally accepted for sporadic and familial forms of AD. However, it remains unclear whether a similar pattern of disease progression occurs in people with DS due to the limited number of in vivo neuroimaging studies, particularly functional MRI, in this population.

We sought to address these gaps in knowledge through the use of neuroimaging studies involving individuals with DS in both preclinical and clinical stages of AD. First, we measured neurodegeneration in the MTL of people with DS and tested whether it was related to MCI/AD clinical diagnosis, episodic memory performance, and plasma neurofilament light chain protein (NfL), which is a peripheral measure of axonal injury. We found that plasma NfL levels mediated the relationship between atrophy in both the anterolateral entorhinal cortex and hippocampus and verbal free recall. Next, we assessed resting state functional connectivity in the DMN in cognitively stable individuals with DS, some of whom were later diagnosed with dementia. We found that lower connectivity between distant hubs of the DMN predicted future dementia diagnosis and faster cognitive decline. Finally, we investigated how MTL functional connectivity was related to MCI/AD clinical diagnosis, memory impairment, and tau accumulation in people with DS. We found that greater MTL connectivity was present in those with MCI-DS and was associated with worse memory and possibly greater tau deposition. Together, these findings highlight the distinct timing of the neurobiological changes occurring in two brain networks uniquely targeted by AD pathology and suggest that altered brain structure and organization may impact the clinical manifestation of this neurodegenerative disease in individuals with DS.