Alzheimer’s Disease is characterized by the loss of neurons in the cerebral cortex and hippocampus. Massive losses of neurons can physically cause shrinkage of these regions of the brain.

One might ask how does Alzheimer’s Disease differ from normal aging? What are the causes of disease? When does it strike and how does it progress? And most importantly, are there good treatments out there? Or a near-term set of late stage clinical candidates?

This is the second article of a three-part series that attempts to address all the above questions with a balanced perspective.

Since its discovery around the turn of the 20th century, the root cause of Alzheimer’s Disease has largely remained a mystery. While familial cases have been linked to specific genes, the majority of cases are sporadic forms of the disease that present similar symptoms and pathological hallmarks. Over 100 years after the first case of Alzheimer’s Disease was characterized we still have not developed a therapeutic capable of halting or reversing disease progression. This is probably due, in large part, to our incomplete understanding of the actual cause of Alzheimer’s Disease.

There are many current working hypotheses about the causes of the disease across the Alzheimer’s research community, some of which are considered to be more mainstream than others. In this segment, we will offer brief descriptions of a sampling of some of these hypotheses.

 

 

Figure 1a: A depiction of a network of neurons that serve as the brain’s wiring system to relay electrical signals. (Image courtesy of the National Institute on Aging/National Institutes of Health)

Figure 1b: A close-up view of a synapse showing how neurotransmitter molecules are released from the pre-synaptic neuron, cross the gap, and bind to receptors on the post-synaptic neuron to transmit the signal onward. (Image courtesy of the National Institute on Aging/National Institutes of Health)

Before introducing these hypotheses, it is necessary to revisit some of the basics of neuronal physiology that were covered in Part 1 of this series. Neurons act as a network of wires and circuits in the brain and central nervous system to transmit messages through electrical impulses and chemical signals. The signal is transmitted from the neuron’s main cell body down the length of the axon until it reaches the end of the neuron. There is a tiny gap between neuronal connections called a synapse (Figure 1b). A specific chemical signaling molecule, or neurotransmitter, is used to bridge this gap and carry the message onward to the next neuron in the network.

Figure 2: Timeline of select Alzheimer’s Disease hypotheses that have emerged over the past 50 years.

Some of the More Prominent Hypotheses in the Alzheimer’s Field

CHOLINERGIC HYPOTHESIS
Mid-1970s to Late-1990s

Studies in the 1960s began looking for neurochemical abnormalities in the brains of Alzheimer’s patients. By the 1970s, evidence suggested that levels of a neurotransmitter called acetylcholine (ACh), used by certain neurons (known as cholinergic neurons), were reduced in Alzheimer’s patients. As it became clear that ACh plays an important role in learning and memory, researchers investigated ways to increase ACh levels. In a healthy individual, ACh is released in the synapse at high levels and then degraded very quickly as a means to carefully regulate signaling events in the brain. The most logical way to increase ACh levels in Alzheimer’s patients was to develop drugs designed to slow the rapid degradation of ACh. By the late 1990s it became clear that dysfunction of cholinergic neurons may not be the direct cause of dementia, but rather an effect of disease progression. Many of the drugs currently approved to treat the symptoms of Alzheimer’s Disease and dementia help to slow the degradation of ACh.

AMYLOID HYPOTHESIS
Mid-1980s to Present

This hypothesis postulates that the accumulation of extracellular amyloid plaques, composed of aggregated Aß proteins, is the toxic entity that ultimately induces neuronal death. The amyloid hypothesis is still one of the most important hypotheses in the Alzheimer’s field and suggests that blocking amyloid formation or the removal of amyloid plaques could prevent or slow neuronal death. However, there is increasing evidence that amyloid plaques are also found in elderly individuals with no signs of Alzheimer’s Disease and drug candidates that target Aß continue to fail in Phase 3 clinical trials.

TAU HYPOTHESIS
Late-1990s to Present

Tau is a normally soluble protein found in the axons of neurons that helps maintain transport processes inside of cells. Abnormally high levels of a chemically modified form of the tau protein are thought to enable the aggregation of other tau proteins in a seeding effect that creates long filaments which further aggregate into neurofibrillary tangles (NFTs). NFTs can disrupt or “choke” off normal transport processes inside of neurons ultimately leading to neuronal death and neurodegeneration.

Figure 3: Representation of neurofibrillary tangles (NFTs), composed largely of aggregated tau proteins, that appear inside of dying neurons. (Image courtesy of the National Institute on Aging/National Institutes of Health)

Recent evidence suggests that tau protein aggregates can be transported between nerve cells via the network of connections between neurons further enabling the seeding effect through the neural network. The appearance of NFTs tend to correlate more closely from a timing perspective with cognitive decline than the appearance of amyloid plaques. Again, it remains unclear if tau is the causative agent, or if NFTs are just another marker of the greater pathologic process.

APOE
Early-1990s to Present

The APOE gene encodes Apoliprotein E, which is involved in transporting cholesterol, lipids, and plays a role in injury repair in the brain. Different alleles or isoforms of the gene represent some of the highest genetic risk factors for Alzheimer’s Disease. Carriers of the ε4 allele (ApoE4) are at increased risk of developing Alzheimer’s while individuals with the ε2 allele (ApoE2) have a decreased risk of disease. ApoE4 homozygotes (people with two copies of the ε4 allele) have a >50% risk factor of developing Alzheimer’s over the course of their lifetimes while ApoE3 and ApoE4 heterozygotes (1 copy of either allele) each have a 20–30% risk factor respectively. Apolipoprotein E has been characterized to bind cell-surface receptors, for the delivery of lipids to cells, and the Aβ peptide. It has been hypothesized that the various isoforms of ApoE may interact with Aβ differently resulting in altered roles that could lead to greater aggregation or clearance of Aβ in the brain. With that said, there is also evidence of effects independent of Aβ making it appear that ApoE4 may increase the risk of Alzheimer’s by multiple pathways.

A Sampling of Some Recent Emerging Hypotheses:

MICROGLIAL (INFLAMMATION) HYPOTHESIS
Early 2010s to Present

This hypothesis suggests that microglia, a type of cell critical for early brain development and the maintenance of healthy neurons throughout adulthood, play a central role in Alzheimer’s Disease. Very early in development, microglia have been characterized to help shape the neuronal circuitry of the brain through processes that involve both supporting the maturation of neurons and intentionally pruning, or destroying, certain neuronal connections. Later in life, and throughout adulthood, microglia function as the brain’s immune system, similar to white blood cells, by scavenging and engulfing cellular debris, damaged or dead neurons, and infectious pathogens.

Figure 4: Illustration of a microglial cell and a neuron. Microglia accounts for 10-15% of all cells in the brain. They reside in close proximity to neurons with the primary role of maintaining a safe environment by cleaning up debris and engulfing pathogens.

• Some in the research community propose that inflammation in the brain, induced by:  infection; trauma; or possibly the formation of amyloid plaques, can activate microglia and that neurons are destroyed as collateral damage.
• Others have provided evidence that environmental assault early in development due to: infection; trauma; or even changes in microbiota (the populations of microbes that live within and on the human body), can alter the behavior of microglia to display more “destructive tendencies,” such as excessive pruning of neuronal connections, throughout adulthood. Over time these actions can lead to a disease state.
• Very recent evidence suggests that certain genetic mutations can cause microglia to be less effective in their role of cleaning up cellular debris, including amyloid plaques. This view, in parallel with the Amyloid Hypothesis, posits that microglia normally play a key role in preventing the build-up of amyloid plaques.
More research will be necessary to untangle the exact role(s) of microglia in the context of Alzheimer’s Disease.

MICROBIAL HYPOTHESIS
2009 to Present

This hypothesis suggests that the origins of plaques may be remnants of previous infections in the brain, that amyloid plaques are intentionally formed as a defense mechanism functioning to surround and trap microbes or viruses. Evidence from animal models and the characterization of Alzheimer’s-like pathologies in individuals who have previously had viral infections in their brains support this hypothesis. While many researchers in the field appear to be intrigued by these recent results, more evidence of both a preclinical and clinical nature will be required to further substantiate the theory.

MITOCHONDRIAL CASCADE HYPOTHESIS
2004 to Present

This hypothesis suggests that the cause of Alzheimer’s Disease starts with mitochondrial dysfunction in neurons. Mitochondria are organelles found in the cells of all higher organisms that function as the “power house” responsible for producing the bulk of the energy required by cells.

Figure 5: On the left is a depiction of a healthy mitochondrion, on the right, an unhealthy mitochondrion. (Image courtesy of the National Institute on Aging/National Institutes of Health)

The mitochondrial cascade hypothesis proposes that both hereditary and environmental factors contribute to a “predisposed risk” that an individual’s mitochondria will not remain optimally active and highly efficient later in life. It suggests that individuals with less active mitochondria will experience more rapid aging of their brains, which may include the formation of amyloid plaques, and will be more likely to experience neuronal loss and dementia at an earlier age.

INSULIN SIGNALING HYPOTHESIS
Early 2000s to Present

Individuals with Type 2 diabetes are nearly twice as likely to develop Alzheimer’s Disease. There are multiple hypotheses that suggest links between insulin signaling and Alzheimer’s Disease. Some researchers report that insulin deficiency is the culprit while others suggest that hyperinsulemina (or over production of insulin) is to blame. In the latter case, insulin-degrading enzyme is thought to be connected to Alzheimer’s since it acts to degrade both insulin and Aß. While the mechanistic link has yet to be uncovered, the association between the two disorders remains clear.

The above hypotheses are only a sampling of the many theories on the root cause of Alzheimer’s Disease. It is important to introduce these ideas focused on elucidating the origins of disease and potential mechanisms of pathogenesis since this is the way in which new potential drug targets will be discovered. Once a viable drug target has been identified, researchers can develop approaches to slow or possibly even reverse disease progression. The third and final segment of this three-part series will: review the few available drugs that are FDA-approved; highlight several drugs currently in the pipeline; cover select therapeutics that failed in late-stage clinical trials; and introduce some of the diagnostic approaches currently in use or under development.


CONTRIBUTORS TO THIS ARTICLE INCLUDE

Niranjan Bose, Senior Director, bgC3, LLC

Matthew Clement, Associate Consultant, C2R Corporation

Mike Poole, Director, Global Health, Bill & Melinda Gates Foundation

Cognition Studio

David Ehlert, Director of Science Storytelling

Jared Travnicek, Senior Medical Illustrator + Animator

Chad P. Hall, Senior Designer


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