Age at onset reveals different functional connectivity abnormalities in prodromal Alzheimer’s disease

Age at symptom onset (AAO) underlies different Alzheimer’s disease (AD) clinical variants: late-onset AD (LOAD) is characterized by memory deficits, while early-onset AD (EOAD) presents predominantly with non-memory symptoms. The involvement of different neural networks may explain these distinct clinical phenotypes. In this study, we tested the hypothesis of an early and selective involvement of neural networks based on AAO in AD. Twenty memory clinic patients with prodromal AD (i.e., mild cognitive impairment with an AD-like cerebrospinal fluid profile) and 30 healthy controls underwent a cognitive evaluation and a resting state functional MRI exam. Independent component analysis was performed to assess functional connectivity (FC) in the following networks: default mode, frontoparietal, limbic, visual, and sensorimotor. Patients were stratified into late-onset (pLOAD) and early-onset (pEOAD) prodromal AD according to the AAO and controls were stratified into younger and older groups accordingly. Decreased FC within the default mode and the limbic networks was observed in pLOAD, while pEOAD showed lower FC in the frontoparietal and visual networks. The sensorimotor network did not show differences between groups. A significant association was found between memory and limbic network FC in pLOAD, and between executive functions and frontoparietal network FC in pEOAD, although the latter association did not survive multiple comparison correction. Our findings indicate that aberrant connectivity in memory networks is associated with pLOAD, while networks underlying executive and visuo-spatial functions are affected in pEOAD. These findings are in line with the hypothesis that the pathophysiological mechanisms underlying EOAD and LOAD are distinct.