Brain cells that build resilience against Alzheimer’s
Not everyone with amyloid plaques in the brain develops dementia. Some people reach a hundred years old with Alzheimer’s hallmarks but without memory loss. Researchers have now identified which brain cells are responsible.
Alzheimer’s disease does not progress the same way in everyone. Some octogenarians live without dementia despite amyloid-beta protein deposits in their brains. Centenarians sometimes show the same deposits yet remain cognitively intact. What protects them?
An international team examined brain tissue from octogenarians with and without dementia, and from cognitively intact centenarians. They used two modern techniques: spatial transcriptomics (measuring gene activity at precise locations in tissue) and single-nucleus RNA sequencing (reading the genetic activity of individual cells). The results were published in Nature Medicine.
Microglia in two states
At the centre of the study are microglia, the brain’s resident immune cells. They clear waste, respond to damage and keep neurons healthy. The researchers identified six spatial patterns in brain tissue that reflect a kind of timeline of Alzheimer’s progression. At a specific point along that timeline, microglia shift their behaviour: from an inflammatory response to an antigen-presenting state, in which they relay information to the immune system about what is going wrong.
Octogenarians without dementia lacked that second microglial state. Centenarians had it activated, but uncoupled from the accumulation of tau, a second harmful protein that normally follows amyloid. That uncoupling appears to be a key factor in resilience at very old age.
Two types of protection, one shared target
Notably, the two resilient groups seem to protect themselves in different ways. That suggests multiple routes to cognitive resilience exist, not one universal path. The researchers describe the transition between microglial states as a candidate therapeutic target. Whether that translates into clinical benefit remains to be established.