A new study identifies distinct cellular differences in patients with sporadic early-onset Alzheimer’s disease (AD) and late-onset AD. The findings implicate specific transcription factors, intracellular signaling pathways, and candidate cis-regulatory elements (cCREs). Hallmark neuropathological traits of late-onset AD and sporadic early-onset AD include aggregation of tau protein and amyloid-β peptides – but the presentation of each subtype differs clinically. In early-onset AD, symptoms appear before the age of 65, progress faster, and are more likely to be atypical. These distinctions suggest the subtype emerges from a different molecular landscape. Andi Liu and colleagues analyzed postmortem samples of the prefrontal cortex, entorhinal cortex, and hippocampus from 4 people with early-onset AD and 5 people without it. By creating an RNA and DNA compendium of 76,173 cell nuclei, they characterized genetic and regulatory signatures associated with early-onset AD. They found early-onset AD-specific changes for 8 transcription factors in relevant glial cells, such as RFX4 in astrocytes and IKZF1 in microglia. They also pinpointed 25 types of disrupted intracellular communications between glial cells and neurons. The team further defined 33 cCREs in the brain regions tied to early-onset risk genes that overlapped with late-onset risk genes.

Mass General Brigham researchers found that hyperphosphorylated tau, the main component of pathological tangles in Alzheimer’s disease, may have serve to help protect the brain from infection

In brief:  

How the brain tracks distance: MPFI scientists identified how hippocampal neurons encode distance traveled without relying on visual cues.  

A new neural code: Neuronal activity patterns act as a two-phase code to mark movement onset and track elapsed distance. 

Why it matters: These patterns may help the brain stitch moment-to-moment experiences into a memory of an event. 

Alzheimer’s relevance: The work may offer insight into early navigation problems commonly seen in Alzheimer’s disease.