Genetics of Alzheimer’s disease: First identification of a strong recessive component

A new study from deCODE genetics and Collaborators is the first to uncover a strong recessive component in Alzheimer’s disease.

deCODE genetics/Amgen, and collaborators from Iceland, USA, UK, Denmark, Norway, and Sweden recently published the study: “Homozygosity for a missense variant in R47H in TREM2 and the Risk of Alzheimer’s Disease”, in New England Journal of Medicine¹. This study marks a significant milestone by identifying a strong recessive component in the genetics of Alzheimer’s disease.

In 2013, deCODE genetics and collaborators were first to associate a sequence variant, R47H, in the TREM2 gene with Alzheimer’s disease². Disrupted Aβ clearance has been associated with R47H and the current study¹ reveals an inheritance pattern deviating from the additive model with a strong recessive component, with high Alzheimer’s risks in homozygotes (R47H/R47H) and compound heterozygotes (R47H/R62H).

Alzheimer's disease is a common neurodegenerative disorder with high heritability. While autosomal dominant forms of Alzheimer’s exist—where specific sequence variants in APP, PSEN1, and PSEN2 genes lead to overproduction and/or aggregation of Aβ, causing plaque deposition and Alzheimer’s disease with near-complete penetrance—R47H in TREM2 differs in its mechanism and inheritance pattern. Rather than contributing to Aβ overproduction and/or aggregation, R47H disrupts Aβ clearance, resulting in the accumulation of amyloid plaques and a greatly increased risk of Alzheimer’s disease in homozygotes (R47H homozygotes odds ratio, 97.1 [95% CI, 23.5 to 401.1]) and R47H-R62H compound heterozygotes (odds ratio, 10.0 [95% CI, 4.2 to 23.9]). This study is the first to uncover a strong recessive component in Alzheimer’s disease.

The very high risk in R47H homozygotes underscores the necessity for early intervention if treatments such as Aβ-removing antibodies or TREM2 agonists are shown to have efficacy at the preclinical stage.