APOE4 has been shown to increase neuronal excitability in the hippocampus of mice prior to the onset of cognitive symptoms associated with Alzheimer’s disease. Research conducted by the Gladstone Institutes indicates that young mice carrying the human APOE4 allele exhibit heightened interictal spikes (IIS) in specific hippocampal regions compared to their APOE3 counterparts. These spikes are linked to poorer performance on cognitive tests later in life, suggesting that the pathological processes associated with Alzheimer’s may begin much earlier than previously understood.

The study’s findings highlight the mechanistic role of Nell2, a neuronal protein that, when knocked down, mitigates the hyperexcitability and morphological changes observed in APOE4-expressing neurons. This discovery is significant as it provides insight into the early neurophysiological changes that precede cognitive decline, reinforcing the notion that Alzheimer’s pathology is not solely a late-stage phenomenon. The researchers demonstrated that young E4-KI mice, despite normal cognitive function, showed increased IIS rates, which correlated with significant spatial learning deficits as they aged, underscoring the predictive nature of early neuronal excitability.

The implications of this research are substantial for the field of Alzheimer’s therapeutics. By identifying Nell2 as a potential target for intervention, the study opens avenues for developing strategies aimed at reversing or preventing the hyperexcitability associated with APOE4. This could shift current research paradigms towards early intervention strategies that address neuronal dysfunction before the onset of overt cognitive symptoms, potentially altering the trajectory of Alzheimer’s disease progression and improving healthspan in at-risk populations.

Source: lifespan.io