Elevated functional magnetic resonance imaging activity in cognitively normal participants predicts future dementia

As individuals age, they are more likely to show increased functional MRI (fMRI) activity, particularly in frontal regions. This has been interpreted as a compensatory mechanism, yet the very need to draw upon such resources indicates increasing failures of brain systems. Almost all work addressing theoretical models explaining these patterns has been cross-sectional, with minimal work testing how elevated fMRI activity predicts future cognitive trajectories. Further, although often viewed as ageing, there is increasing evidence that subtle fMRI changes may represent the earliest manifestation of neurodegenerative conditions such as Alzheimer's disease. One hundred nine individuals completed a Stroop colour/word task during fMRI data acquisition. Analyses focused on differences between trials where the colour and word were incongruent (the word red written in blue) relative to congruent trials (the word blue written in blue). At baseline, participants also underwent amyloid positron emission tomography imaging and APOE genotyping. Individuals had longitudinal clinical follow-up (mean 6.8 years) with 15 individuals reaching the threshold of clinically defined cognitive impairment. Across the entire cohort, several brain regions, including dorsolateral prefrontal cortex, anterior cingulate cortex, and lateral temporal and parietal regions, were more active on conflict trials. At the individual level, increases in activity were related to changes in reaction time, with those experiencing greater conflict having greater evoked activity. Further, individuals who later developed dementia had greater activity at baseline than their peers who remained cognitively normal despite there being no differences in accuracy (t = 0.23, P = 0.82) or reaction time (t = 0.94, P = 0.35) in the Stroop task nor differences in mini-mental state examination (t = 0.06, P = 0.95) or a neuropsychological composite (t = -0.99, P = 0.32). Individuals who progressed were more likely to be amyloid positive (χ ² = 26.71, P = 0.000002) and carriers of the APOE ε4 allele (χ ² = 4.81, P = 0.03). The current work suggests that, although compensatory in nature in the short term, increased activation of frontal and parietal control regions during attentional control tasks is indicative of underlying declines in brain health. The larger implications are 2-fold. Undetected neurodegenerative disease pathology biases our understanding of what constitutes healthy ageing. Further, alterations in brain function occur well in advance of clinically detectable cognitive change, emphasizing the need to intervene with disease modifying therapies early in the disease course.