Your brain has multiple independent systems for clearing the beta-amyloid that accumulates in Alzheimer's disease.
7 of the most studied genetic regulators of beta-amyloid clearance, microglial function, and amyloid precursor protein trafficking.
The Biology
APOE affects Alzheimer's risk largely through its role in binding and transporting beta-amyloid, but the brain's clearance systems involve more than one protein. Microglia, the brain's immune cells, sense, engulf, and degrade amyloid aggregates. Endocytic pathways process and recycle cellular waste. Complement proteins tag amyloid for removal. Sorting receptors steer amyloid precursor protein away from the pathway that produces beta-amyloid.
What Varia Analyzes
7 variants across these systems. TREM2 R47H (rs75932628), a rare microglial receptor variant whose carriers have Alzheimer's risk comparable to one copy of APOE4 in published studies; CLU, clusterin (rs11136000), involved in beta-amyloid solubilization; PICALM (rs3851179), a regulator of endocytic amyloid clearance; BIN1 (rs7561528), associated with tau pathology; CR1 (rs6656401), a complement receptor involved in amyloid clearance; ABCA7 (rs3764650), an ABC transporter involved in microglial lipid efflux; and SORL1 (rs641120), a neuronal sorting receptor that traffics amyloid precursor protein, where reported associations for this variant are inconsistent across studies.
Why It Matters
Most of these loci came from large genome-wide association studies of Alzheimer's disease, and each contributes a small amount on its own; none is deterministic. Some alleles are associated with lower risk: the T allele at CLU (rs11136000) and the T allele at PICALM (rs3851179). Read alongside APOE in Domain I, these add context to the APOE result rather than replace it.
Key Sources
- Guerreiro R, et al. TREM2 variants in Alzheimer's disease. N Engl J Med. 2013.
- Harold D, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009.
- Lambert JC, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet. 2009.
- Rogaeva E, et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007.