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APOE encodes a secreted apolipoprotein involved in lipid metabolism. It is best known for its three major alleles—APOE2, APOE3, and APOE4 —with APOE4 increasing the risk for Alzheimer’s disease and APOE2 reducing it. Every person has an APOE genotype determined by pairs of these alleles: APOE3/E3 (the most common), APOE3/E4, APOE3/E2, APOE2/E4, APOE4/E4, or APOE2/E2. Other variants , many of them rare, have also been studied. Some have been tied to AD, to other neurological disorders, and/or to peripheral conditions, including alterations of lipid metabolism, cardiovascular or kidney disease.
APP encodes amyloid precursor protein, a transmembrane protein which is cleaved to form amyloidogenic Aβ peptides. Mutations in APP are associated with familial forms of early onset Alzheimer's disease as well as with Cerebral Amyloid Angiopathy (CAA). Pathogenic mutations generally alter processing by secretases, leading in an overall increase in Aβ production and/or a change in the ratio of specific Aβ peptides.
MAPT encodes the microtubule associated protein tau, a protein central to Alzheimer’s disease neuropathology. MAPT mutations are not linked to familial forms of AD, but can cause frontotemporal dementia (FTD) and several other tauopathies. The pathogenic mutations, which can be either exonic or intronic, generally alter the relative production of tau isoforms and lead to changes in microtubule assembly and/or the propensity of tau to aggregate.
PSEN1 encodes presenilin-1, a subunit of γ-secretase, the aspartyl protease responsible for Aβ generation. More than 300 mutations in PSEN1 have been reported and mutations in PSEN1 are the most common cause of early onset Alzheimer's disease.
The gene PSEN2 encodes presenilin-2, a subunit of γ-secretase, the aspartyl protease responsible for Aβ generation. Missense mutations in PSEN2 are a rare cause of early onset Alzheimer's disease.
SORLA, the sortilin-related receptor with type-A repeats, also known by its gene name SORL1 and as LR11, is an endosomal sorting receptor involved in APP and Aβ trafficking, among other functions. Multiple studies have associated rare, putative loss-of-function variants in SORL1 with an increased risk of Alzheimer’s disease.
TREM2 encodes Triggering Receptor Expressed on Myeloid Cells 2, a transmembrane receptor that modulates microglial activity and survival. TREM2 variants cause Nasu-Hakola disease (NHD), a rare autosomal recessive early-onset dementia, and may modify the risk of developing Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).