Alzheimer’s Disease (AD) is the most common type of dementia (60% – 70% of dementia cases) and causes aberrant memory, thinking and behavior that progresses over time and ultimately results in death, usually within eight years of noticeable symptom onset. Symptoms generally first appear in people in their 60’s, and in 2015, an estimated 5.3 million Americans suffer from the disease of whom 5.1 million are age 65 and older. AD is currently the sixth leading cause of death in the United States.
There are two broad classes of AD, familial AD (FAD) and sporadic AD (SAD). FAD is relatively rare, accounting for between 1% and 5% of cases, and is characterized by either autosomal dominant inheritance or inheritance of genetic mutations in one or more of three genes, those encoding for: amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2). Inheritance of these genes causes increases in the production of AB42, which is the primary molecule in senile plaques. The etiology of SAD is much less clear, but is believed to derive from interactions between uncertain genetic and environmental risk factors. The best known genetic risk factor for SAD is the inheritance of the epsilon4 allele of the apolipoprotein E (APOE), which increases the likelihood of developing AD by 3 times in heterozygotes and 15 times in homozygotes. Additionally, genome-wide association studies (GWAS) have found 19 additional genetic markers that appear to affect risk. There are currently no known cures for AD, and treatment options are available but largely ineffective.
The current major hypothesis in the field of AD research characterizes AD pathophysiology using the amyloid cascade model. In this framework, amyloid beta (AB) fragments are thought to oligomerize and accumulate extracellularly as plaques, accompanied by tau protein hyperphosphorylation and neurofibrillary tangles, which causes neurotoxic events that result in neurodegeneration. This process starts primarily in the medial temporal lobes and frontal cortices, and eventually spreads throughout the brain.
Given the impact AD has on the general population, a major research effort is underway to better understand the disease and discover more effective treatment options. There are currently greater than 100,000 articles in Pubmed on the etiology, mechanisms, and typology on Alzheimer’s disease. However, there remains much to be discovered, and therapies generated based on this literature have by and large proven ineffective.
How could this be?
Lawrence Goldstein et. al. proposes that our efforts have fallen short partly because research on AD thus far has relied primarily on animal models and non-neuronal human cells to investigate the molecular mechanisms associated with the disease. Animal models are problematic because not one has generated a phenotype that fully characterizes the disease in its many forms, and often requires expressing human genes in a non-human genetic context. Using non-neuronal human cells is also problematic, mainly because they lack many of the most important qualities that make neurons unique, such as: size, ability to generate action potentials, extensive interconnectivity, compartmentalization into axonal and somatodendritic regions, and several others.
Goldstein et. al. suggest that a new era in AD research is underway, and will use human induced pluripotent stem cells (hiPSC). This technique allows human neurons cultivated from people with AD to be reprogrammed to a pluripotent state, which can then be differentiated into a variety of cell types such as neurons, astrocytes, oligodendrocytes, and other brain cells. Given that these cells were derived from people with AD and therefore have higher ecological validity than animal models or non-neuronal human cells, they can be used to more efficaciously test mechanisms of the disease, identify therapeutic targets, and evaluate genetic risk factors.
The use of hiPSCs in AD research is fairly new, but the few articles published thus far are promising. Goldstein et. al. breaks down the state of AD research using hiPSCs into three broad categories: 1) FAD mutations in APP (see above); 2) FAD mutations in PS1 and PS2, and; 3) effects of AB toxicity on different types of neurons. The results of these studies are shared in the table below.
Thus, the use of hiPSCs is an exciting new avenue of research into the possible causes and treatments of AD. However, if this new line of research proves to be the linchpin for finding an effective treatment or cure, there is a broader implication for neuroscientists: how much should we be relying on animal models and non-neural human cultures? To what extent are they useful? Can we devise a sound conceptual framework for deciding between methodologies? These are tough questions that scientists will struggle to answer in the very near term. However, if one branch of science can handle rapid growth and the requirement of choosing between myriad techniques, modern neuroscience is a good bet.
About the author: Daniel Stern is the same as he was for last week’s post, just slightly more rotund post Thanksgiving stuffing.