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 three-part series attempts to address all the above questions with a balanced perspective.

Image courtesy of the National Institute on Aging/National Institutes of Health.

Alzheimer’s Disease is the 6th leading cause of death in the U.S. With an aging population, prevalence of Alzheimer’s Disease in the U.S. is expected to grow from an estimated 4–5M in 2015 to 14M in 2050. It is one of the most costly diseases in wealthy nations because of high medical costs and productivity losses. Globally, it has been estimated that spending in 2016 was $604 billion. In the U.S. alone medical costs were estimated to be $236B in 2016. Productivity losses due to an estimated 15 million people contributing 18.1 billion hours of unpaid assistance to Alzheimer’s Disease and dementia patients has been valued at $221.3 billion each year. Without any advances in treatment or prevention, the economic burden of this disease in the U.S. is projected to reach $1T by 2050.


Alzheimer’s Disease is a neurodegenerative disease (a set of hereditary or sporadic conditions that are both incurable and progressive) that has been characterized by the loss of function of neurons and ultimately neuronal death. Neurons are nerve cells that relay messages throughout the brain and central nervous system serving as a network of wires and circuits. Nerve impulses traverse the length of neurons down long tail-like extensions called axons. When the impulse reaches the end of an axon, it is received by the next neuron in the network by short tree-like branches called dendrites. This junction point where the axon of one neuron meets the dendrites of another is called a synapse. From here the process is repeated over and over as the impulse is transmitted from one neuron to the next propagating the signal throughout the network (Figure 2a).  

Figure 2: On the left (A) is an illustration of a network of healthy neurons – axons and dendrites are labeled accordingly; on the right (B) is a representation of a diseased network of neurons, note the presence of amyloid plaques and the atrophied axons and dendrites. Neurofibrillary tangles are difficult to see in this representation since they reside inside of neurons. (Images courtesy of the National Institute on Aging/National Institutes of Health.)

Approximately 25% of Alzheimer’s Disease cases can be classified as familial arising from genetic mutations in 5 genes. About 75% of all Alzheimer’s Disease cases have no known cause. There is no direct evidence that environmental factors cause the disease, although twin studies have implicated a combination of environmental factors in conjunction with a predisposed genetic background.

As the disease progresses, an increasingly high number of neurons die resulting in neuronal and tissue losses in the cerebral cortex and hippocampus. Massive losses of neurons can physically cause shrinkage of these regions of the brain (Figure 1).

Pathological hallmarks of Alzheimer’s Disease (for both familial and non-familial forms) include the appearance of amyloid plaques outside of neurons (Figure 2b) and neurofibrillary tangles inside of neurons. Amyloid plaques are thought to result from the misfolding and aggregation of a small protein called amyloid beta (Aß) while neurofibrillary tangles are believed to be clumps of another protein call tau. Both plaques and tangles are hypothesized to be toxic to neurons and ultimately result in neuronal death causing numerous breaks in the signaling network (Figure 2b). More details on the hypotheses on the cause of Alzheimer’s Disease will be covered in Part 2 of this series


Figure 3: Adapted from Jack, Knopman, Jagust, et. al (2010) and Sperling, Jack and Aisen (2011).

Having covered the hallmarks of pathology and disease progression, it is important to discuss the current thinking about the origins of Alzheimer’s Disease. Over the years, several hypotheses have been tested and some have been rejected (such as aluminum as a cause of disease) along the way.

Stay tuned for the next part of this three-part series, which will cover the different hypotheses and etiology mechanisms.


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


  1. National Institute on Aging, National Institutes of Health. (2016). Alzheimer’s Disease Fact Sheet. NIH Publication No. 16-AG-6423.
  2. Alzheimer’s Association, 2013 Alzheimer’s Disease Facts and Figures. Alzheimer’s & Dementia, 2013; 9(2).
  3. Alzheimer’s Association. 2016 Alzheimer’s Disease Facts and Figures. Alzheimer’s & Dementia 2016;12(4).
  4. Duthey 2013, WHO Background Paper 6.11 Alzheimer’s Disease and other Dementias.
  5. Murphy SL, Xu J, Kochanek KD. 2012. “Deaths: Preliminary Data for 2010.” National Vital Statistics Reports; 60(4).
  6. Ciechanover A, Kwon YT. 2015. Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exp Mol Med; 47:e147.
  7. Bird TD. Alzheimer Disease Overview. Initial Posting: October 23, 1998; Last Revision: September 24, 2015.
  9. Fjell AM, McEvoy L, Holland D, Dale AM, Walhovd KB. 2104. Alzheimer’s Disease Neuroimaging Initiative. What is normal in normal aging? Effects of aging, amyloid and Alzheimer’s disease on the cerebral cortex and the hippocampus. Prog Neurobiol; 117: 20–40.
  10. Jack CR, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ. 2010. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol; 9(1): 119–128.
  11. Sperling RA, Jack CR, Aisen PS. 2011. Testing the right target and the right drug at the right stage. Sci Transl Med; 3(111): 111cm33.
  12. Jack CR, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P, Wiste HJ, Weigand SD, Lesnick TG, Pankratz VS, Donohue MC, Trojanowski JQ. 2013. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol; 12(2): 207–216.

Want to read more? Read Part (Two) to this article here