The Alzheimer's Genome
The progression of Alzheimer's disease varies considerably between patients. Is this a matter of random chance in the complex dysfunction of a complex system, or should researchers be looking more closely at genetic and epigenetic differences between patients as a contributing cause of this variability? Researchers here argue for this conclusion based on what is presently known of the heritability of Alzheimer's disease risk and specific genetic variants that are correlated with Alzheimer's disease risk.
Alzheimer's disease (AD) has traditionally been considered first and foremost a neurodegenerative condition. This neuron-centric view of AD is not wholly unjustified, as synapse and neuronal loss are cornerstone features of the worsening cognitive outcomes associated with disease progression.In addition, two primary histopathological hallmarks, extracellular β-amyloid deposition and intraneuronal neurofibrillary tangles of hyperphosphorylated tau protein, have informed much of the research on AD pathogenesis and are still fundamental scoring criteria of present molecular attempts to stage disease trajectory. However, we now know that the disease is more multifaceted than this, comprising different cell types, inflammatory overloads, the vasculature, and uniquely vulnerable brain regions, among others. Therefore, the limited success of AD therapies, which have focused largely on mitigating β-amyloid pathology, may stem from our inability to tackle the complexity of the disease and the heterogenicity of those suffering from it.
The genome holds the key to many of these individual differences. Genetics account for up to 58%-79% of AD risk, and about 75 susceptibility loci have been discovered to date. For comparison, the genetic component of Parkinson's disease is about 15%. In fact, the heritability of AD is so great that parental disease history has been employed to identify AD-by-proxy cases in attempts to increase the power of genetic association studies. Still, it has not been trivial to translate these genetic links into mechanistic breakthroughs and therapeutic targets, as the resulting functional outcomes and causal genes linked to each polymorphism remain mostly unresolved.
Here, we explore how genomic research has advanced the understanding of late-onset AD. This is, for us, the first meaning of the "broken" AD genome, akin to unraveling a code. But various processes centered on our DNA become dysfunctional in AD, imparting an equally significant connotation to the term; i.e., "broken" in this context alludes to the genome as a driver of disease. We primarily highlight findings originating from human datasets, as existing disease models often fail to recapitulate the full pathological spectrum of AD. We recognize the importance of these tools and, when appropriate, reference insights obtained using them. We also identify challenges for the field and discuss strategies for amassing the wealth of genomic information now available for developing therapeutics and clinical tools.