Work on two Turkish families with dementia led to the discovery of one of the most important genetic risk factors yet identified in Alzheimer's disease.
Sequencing of coding regions of the genome has become a costeffective way to identify the genes underlying inherited diseases, including familial dementias. For Dr Rita Guerreiro in Professor John Hardy's lab, an analysis of Turkish families affected by early-onset frontotemporal dementia led to the identification of a risk factor with the second biggest impact on disease after apolipoprotein E (ApoE) and sparked a flurry of interest in the role of inflammation in Alzheimer's disease.
Through sequencing, Professor Hardy and colleagues discovered that three family members with dementia had mutations in a gene known as TREM2. Notably, TREM2 was known to be involved in regulating the activity of microglia, the brain's immune cells.
With evidence growing of an inflammatory component to Alzheimer's disease, Dr Guerreiro then carried out a routine check on sequence data from sporadic Alzheimer's disease cases. To her surprise, she discovered TREM2 variants in a significant number of patients. Systematic genotyping of more than 1000 patients revealed TREM2 variants in 22 cases but just five controls. TREM2 variants increase the risk of developing Alzheimer's disease around threefold, about as much as the well-recognised ApoE4 risk factor (though TREM2 variants are much less common).
Perhaps most exciting is the insight the discovery provides into the mechanisms of disease. There has been growing interest in inflammation in Alzheimer's disease, particularly as genome-wide sweeps for genetic risk factors have implicated several genes involved in immune responses.
Signalling through TREM2 is thought to dampen down microglia. Full mutations may leave it unable to prevent runaway inflammatory responses, leading to rapid neurodegeneration and early-onset dementia in people inheriting two copies of the faulty gene. The Alzheimer's-linked variants may mean that microglia are more active than is ideal, and respond too aggressively to β-amyloid, increasing the risk of Alzheimer's disease.
TREM2 is certainly the strongest hint yet that neuroinflammation is an important feature of Alzheimer's disease - and a potential route to new therapies, perhaps by boosting TREM2 levels or more generally by targeting other aspects of the inflammatory response.