A century of questions: Retrospective study of the controversy and efficacy of Alzheimer's disease models

Alzheimer’s disease (AD) has been a devastating challenge to the research, medical, and public community for more than a century. In 1906, Alois Alzheimer characterized it as a neurodegenerative disease associated with progressive cognitive and memory impairment. Today, the only way to conclusively diagnosis AD is by autopsy that shows hallmark accumulation of proteins throughout the brain as 1) senile plaques from extracellular accumulation of amyloid-β peptide (Aβ) and 2) neurofibrillary tangles from aberrant posttranscriptional modification of the microtubule-associated protein tau. The ability of an extra copy of APP carried on chromosome 21 to cause early onset AD in individuals with Down syndrome who are trisomic for chromosome 21 led to the amyloid cascade hypothesis. This hypothesis states that abnormal processing of the amyloid precursor protein (APP) to Aβ is both necessary and sufficient for the neurotoxic cascade that leads to neuron death and brain atrophy in the hippocampus, temporal lobe and regions of the neocortex.1 Only after the amyloid cascade hypothesis was proposed in the early 1990’s had research made significant headway on deciphering the molecular mechanism of disease. Many pre-clinical studies with drugs targeting APP or Aβ have shown efficacy in vivo and in vitro, but have failed in later clinical trials. Now, many will argue that the hypothesis “is intellectually flawed“ and is impeding progress. The question to be considered is whether the pharmacological industry has wasted time and money on a faulty hypothesis or whether they have been misled by model systems that fail to appropriately mimic the disease at a level necessary for translational results. It can be argued that the greatest source of debate that seems to prevent the field from moving forward remains with the experimental method: How do we generate a model system that appropriately recapitulates a disease which we do not fully understand? In this paper, I will address the controversy and debate surrounding the century-old study of AD by reviewing the leading hypothesis of disease, the relevancy and efficacy of current and past model systems, and the advantages and disadvantages of in vitro vs. in vivo analysis for clinical outcomes. By doing so, I will provide a retrospective timeline of AD research efforts and a concluding argument for the diversification of models that could allow investigators a) to collaborate on a national and international scale, b) reach a consensus as to whether neurodegeneration and neuron death are a necessary endpoint of disease c) identify new therapeutic targets and biomarkers shared among multiple model systems d) establish a standard neuropatholgical examination criteria and genotype-to-phenotype analysis for human and animal models, e) address AD-specific pathologies, nondegenerative pathologies and other proteinopathies, of this multifactorial disease in vivo.