Neuronal dysfunction in specific brain regions or across distributed brain networks is a known feature of Alzheimers disease. An often reported finding in the early stage of the disease is the presence of increased functional MRI (fMRI) blood oxygenation level-dependent signal under task conditions relative to cognitively normal controls, a phenomenon known as hyperactivation. However, research in the past decades yielded complex, sometimes conflicting results. The magnitude and topology of fMRI hyperactivation patterns have been found to vary across the preclinical and clinical spectrum of Alzheimers disease, including concomitant hypoactivation in some cases. These incongruences are likely due to a range of factors, including the disease stage at which the cohort is examined, the brain areas or networks studied and the fMRI paradigm utilized to evoke these functional abnormalities. Additionally, a perennial question pertains to the nature of hyperactivation in the context of Alzheimers disease. Some propose it reflects compensatory mechanisms to sustain cognitive performance, while others suggest it is linked to the pathological disruption of a highly regulated homeostatic cycle that contributes to, or even drives, disease progression. Providing a coherent narrative for these empirical and conceptual discrepancies is paramount to develop disease models, understand the synergy between hyperactivation and the Alzheimers disease pathological cascade and tailor effective interventions. We first provide a comprehensive overview of functional brain changes spanning the course from normal ageing to the clinical spectrum of Alzheimers disease. We then highlight evidence supporting a close relationship between fMRI hyperactivation and in vivo markers of Alzheimers pathology. We primarily focus on task-based fMRI studies in humans, but also consider studies using different functional imaging techniques and animal models. We then discuss the potential mechanisms underlying hyperactivation in the context of Alzheimers disease and provide a testable framework bridging hyperactivation, ageing, cognition and the Alzheimers disease pathological cascade. We conclude with a discussion of future challenges and opportunities to advance our understanding of the fundamental disease mechanisms of Alzheimers disease, and the promising development of therapeutic interventions incorporating or aimed at hyperactivation and large-scale functional systems.

Background

Both aging and Alzheimers disease (AD) affect brain networks, with early disruptions occurring in regions involved in episodic memory. Few studies have, however, focused on distinguishing region-specific effects of AD-biomarker negative normal aging and early amyloid- and tau pathology on functional connectivity. Further, longitudinal studies combining imaging, biomarkers, and cognition are rare.

Methods

We assessed resting-state functional connectivity (rsFC) strength and graph measures in the episodic memory network including the medial temporal lobe (MTL), posteromedial cortex (PMC), and medial prefrontal cortex alongside cognition over two years. For this preregistered study, we included 100 older adults who were amyloid- and tau-negative using CSF and PET measurements to investigate normal aging, and 70 older adults who had longitudinal CSF data available to investigate functional changes related to early AD pathology. All participants were cognitively unimpaired older adults from the PREVENT-AD cohort. We used region of interest (ROI)-to-ROI bivariate correlations, graph analysis, and multiple regression models.

Results

In the amyloid- and tau-negative sample, rsFC strength within PMC, between parahippocampal cortex and inferomedial precuneus, and between posterior hippocampus and inferomedial precuneus decreased over time. Additionally, we observed a longitudinal decrease in global efficiency. Further, there was a steeper longitudinal decrease in rsFC and global efficiency with higher baseline age particularly of parahippocampal-gyrus regions. Further, lower rsFC strength within PMC was associated with poorer longitudinal episodic memory performance. In the sample with available CSF data, a steeper increase in rsFC between anterior hippocampus and superior precuneus was related to higher baseline AD pathology. Higher MTL-PMC rsFC strength was differentially associated with episodic memory trajectories depending on APOE4 genotype.

Conclusions

Our findings suggest differential effects of aging and AD pathology. Hypoconnectivity within PMC was related to aging and cognitive decline. MTL-PMC hyperconnectivity was related to early AD pathology and cognitive decline in APOE4 carriers. Future studies should investigate more diverse samples, nonetheless, our approach allowed us to identify longitudinal functional changes related to aging and early AD pathology, enhancing cross-sectional research. Hyperconnectivity has been proposed as a mechanism related to early AD pathology before, we now contribute specific functional connections to focus on in future research.