The genetics of Alzheimer's disease.
Level 5 - mechanism / opinion, no new human data
Narrative review without systematic search or meta-analytic methodology
PubMed 24278680 · doi:10.6064/2012/246210
What was done
This narrative review summarizes genetic discoveries in Alzheimer's disease, distinguishing between early-onset (familial) and late-onset (sporadic) forms and detailing causative mutations, susceptibility loci, and heritability.
What was found
Early-onset Alzheimer's accounts for less than 5% of disease burden, exhibits Mendelian dominant inheritance, and is caused by mutations in APP, PSEN1, and PSEN2. Late-onset Alzheimer's occurs primarily in individuals over 65 years of age with an estimated heritability of 79%. Replicated late-onset risk genes include ABCA7, APOE, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A4A/MS4A4E/MS4A6E, PICALM, and SORL1. Roughly half of the heritability for late-onset disease remains unidentified.
Why it matters
Synthesizing the genetic landscape of Alzheimer's disease clarifies known mechanistic pathways and highlights that substantial missing heritability remains to be found for future therapeutic and preventive targets.
Limits
As a narrative review, the abstract does not report systematic search methods, screening criteria, effect sizes for specific loci, sample sizes, or ancestral diversity of the underlying studies.
Cited by
- supports Familial Alzheimer's disease accounts for less than 5% of Alzheimer's cases, and APP mutations represent less than 1% of Alzheimer's disease cases in humans.