The Effects of Amyloid and Tau on Functional Network Connectivity in Older Populations

Neuroimaging studies suggest that aged brains show altered connectivity within and across functional networks. Similar changes in functional network integrity are also linked to the accumulation of pathological proteins in the brain, such as amyloid-beta plaques and neurofibrillary tau tangles seen in Alzheimer's disease. However, less is known about the specific impacts of amyloid and tau on functional network connectivity in cognitively normal older adults who harbor these proteins. We briefly summarize recent neuroimaging studies of aging and then thoroughly review positron emission tomography and functional magnetic resonance imaging studies measuring the relationship between amyloid-tau pathology and functional connectivity in cognitively normal older individuals. The literature overall suggests that amyloid-positive older individuals show minor cognitive dysfunction and aberrant default mode network connectivity compared with amyloid-negative individuals. Tau, however, is more closely associated with network hypoconnectivity and poorer cognition. Those with substantial amyloid and tau experience even greater cognitive decline compared with those with primarily amyloid or tau, suggesting a potential interaction. Multimodal neuroimaging studies suggest that older adults with pathological protein deposits show amyloid-related hyperconnectivity and tau-related hypoconnectivity in multiple functional networks, including the default mode and frontoparietal networks. We propose an updated model considering the effects of amyloid and tau on functional connectivity in older individuals. Large, longitudinal neuroimaging studies with multiple levels of analysis are required to obtain a deeper understanding of the dynamic relationship between pathological protein accumulation and functional connectivity changes, as amyloid- and tau-induced connectivity alterations may have critical and time-varying effects on neurodegeneration and cognitive decline. Impact statement Amyloid and tau accumulation have been linked with altered functional connectivity in cognitively normal older adults. This review synthesized recent functional imaging literatures in a discussion of how amyloid and tau can interactively affect functional connectivity in nonlinear ways, which can explain previous conflicting findings. Changes in connectivity strength may depend on the accumulation of both amyloid and tau, and their integrative effects seem to have critical consequences on cognition. Elucidating the effects of these pathological proteins on brain functioning is paramount to understand the etiology of Alzheimer's disease and the aging process overall.