My latest work (Dougalis et al., 2025, https://www.biorxiv.org/content/10.1101/2025.01.07.630516v1.full) is diving into the electrophysiological consequences of early Alzheimer’s pathology in human neurons—and the findings are striking. By recording from layer 2/3 pyramidal neurons in iNPH biopsy tissue, we’ve shown that amyloid and tau pathology reshape the electrical behavior of these cells while inhibitory control from layer 1 neurons falters. This gives a direct window into how pathology disrupts neuronal network function.

At the recent Alzheimer’s Association International Conference in Toronto, researchers from the iNPH cohort highlighted complementary insights:

Disease-associated microglia (DAMs):

The balance between DAM-like and homeostatic microglia predicts long-term cognitive decline. High DAM levels correlate with vulnerability, while homeostatic microglia appear protective.

Rare CSF macrophages: Newly identified macrophages in cerebrospinal fluid carry transcriptional signatures strongly linked to AD risk, suggesting immune surveillance in CSF may play a role in disease progression.

By combining electrophysiology with single-cell genomics, we can start connecting the dots: the neurons that misfire in the presence of amyloid and tau are the same ones exposed to shifts in microglial states. Understanding these interactions opens a new avenue for early detection and intervention.

The big picture is clear: living human tissue provides a rare opportunity to link molecular changes, cellular behavior, and cognitive outcomes. Our work shows that neuronal firing changes isn’t just a downstream symptom—it’s a measurable, mechanistic effect of early AD pathology, potentially guided by the surrounding immune environment.