Alzheimer’s disease, the most common form of dementia, is a neurodegenerative disorder that leads to memory loss. As of 2016, Alzheimer's disease affects 5.4 million Americans and is the sixth leading cause of death in the United States (Alzheimer’s Association, 2016). There are two principal forms of the disease. Familial Alzheimer’s disease, a form of Alzheimer's disease that is hereditary, accounts for an estimated 200,000 Alzheimer's disease cases in the United States alone. The remainder of Alzheimer's disease cases is classified as sporadic Alzheimer’s disease. The key difference between early onset familial Alzheimer's disease is that it is the consequence of the malfunctioning mutated genes, whereas late-onset is more likely due to the gradual accumulation of age-related malfunctions (Strobel, n.d.). The prevalence of Alzheimer's disease varies among a myriad of factors such as age, gender, genetics, comorbidities (another disease manifesting itself at the same time--for example, heart disease, which may alter cerebral blood flow, increasing one’s susceptibility to Alzheimer’s), and environment. With our current technology, Alzheimer's disease can only be definitively diagnosed after death through an examination of the brain tissue in an autopsy (National Institute on Aging, n.d.). Although there is no cure for Alzheimer’s, current research shows promise.
Symptoms and Progression
The symptoms of Alzheimer's disease progress over a time period of about 8 to 10 years. There are three main phases of the disease’s progression, each with its own challenges and symptoms. By recognizing the current stage of the disease, physicians can then predict expected symptoms and respond with the respective treatments.
The early stage, or mild stage, of Alzheimer's disease is in many cases the stage during which the disease is first diagnosed. This stage typically persists for 2 to 4 years in which friends and family members start to notice a decline in the patient’s cognitive abilities. Hallmark symptoms of this stage include the following: an inability to recall recent events and information, difficulty with solving problems or making decisions, changes in personality usually resulting in irritability and isolation, difficulty in expressing thoughts, and getting lost or misplacing belongings (Mayo Clinic Staff, 2015).
In the middle stage, or moderate stage, of Alzheimer's disease cognitive sharpness continues to decline and the symptoms experienced in the mild stage are intensified. This stage usually lasts 2 to 10 years, making it the longest stage of the disease. Patients often experience increased difficulty with memory and may need assistance to complete daily activities. Key symptoms of this stage include the following: increasingly poor judgement and confusion, difficulty completing complex tasks, greater memory loss, and stark personality changes such as social withdrawal and suspicion of caregivers (Mayo Clinic Staff, 2015).
In the late stage, or severe stage, of Alzheimer's disease cognitive capacity continues to dwindle and physical ability is gravely impacted. This final stage often lasts 1 to 3 years. In this stage, families often face difficulties in properly caring for the patient which results in nursing home or other long term care facility placement. Core symptoms appearing in this stage include the following: loss in the ability to communicate coherently; reliance on others for personal care such as eating, dressing, and toileting; and inability to function physically including being unable to walk, swallow, and control bladder and bowel movement (Mayo Clinic Staff, 2015).
AD has a strong genetic basis. Perhaps the most well-known mutation implicated in its onset is Apolipoprotein E Epsilon 4 (ApoE-e4). In one study on the link between ApoE-e4 and Alzheimer’s disease, the p-value was under 0.000001, meaning that there is almost certainly a link between that gene and Alzheimer’s (Blacker et al., 1997, p.139).
Familial Alzheimer's disease is linked to Presenilin 1 and 2 genes (PSEN1 and PSEN2, respectively). It produces the catalytic domain of Gamma Secretase, which is involved in cleaving proteins (including Amyloid Precursor Protein, a protein known to be extensively involved in the pathology of Alzheimer’s). Mutants in this gene are loss-of-function mutations, meaning that mutations prevent PSEN1 from completing its normal function. Research indicates that Presenilin proteins play a key role in memory preservation, and their loss can cause symptoms resembling Alzheimer’s disease. In particular, the L435F mutation causes impaired hippocampal long term potentiation; this change is linked to a decreased ability to complete memory-based tasks (Xia et al., 2015).
Though one’s genetics makes a contribution to the onset of Alzheimer’s disease, it is not the only factor responsible. Scientists have found links between Alzheimer’s, stress, and exercise. It has been proposed that through certain pathways stress exacerbates the disease while exercise ameliorates it. Such pathways are either categorized as direct or indirect. One example of a direct pathway is that these processes may alter in cerebral blood flow. Possible indirect pathways include altering the risk of diabetes and hypertension, and through these affecting the brain (Nation et al., 2011, p. 847).
Diet has also been identified as a contributor to the onset, or lack of, Alzheimer’s disease. See the research section for more.
It is clear that there is no single, clear-cut cause of Alzheimer’s disease as there often is in many other disorders. Both genetic and environmental factors play a key role, and researchers are still working to elucidate the connection between these two influences.
Related to the causes described above are the actual mechanisms by which Alzheimer’s disease attacks the nervous system. Mutant genes produce proteins that cannot complete their normal function, and environmental influences create conditions favorable to the onset and development of the disease.
The insidious progression of the symptoms of Alzheimer's disease is exacerbated by the accumulation of two distinct deformities in the brain, neurofibrillary tangles (created by the abnormal accumulation of Tau) and senile plaques (created by the abnormal accumulation of Aβ). The neurofibrillary tangles are found in the cytoplasm of neurons in the entorhinal cortex. The protein Tau, which creates these plaques, particularly in its phosphorylated form (which causes abnormalities in transport and axon function), also makes a key contribution to the damage caused by Alzheimer’s disease (Humpel, 2011). There are two different types of plaques, neuritic and diffuse, that are found in the neocortex of the brain. Neuritic plaques are spherical structures that contain neurites that are surrounded by amyloid--an abnormal protein. The Aβ concentration in the bloodstream is an indicator of the severity of Alzheimer’s disease (McLean et al., 2001, p. 860), indicating its importance in the pathophysiology of the condition. Diffuse plaques lack neurites and have an amorphous appearance (Serrano-Pozo et al., 2011). As the concentration of these deformities increase, healthy neurons begin to become ineffective. As neuronal injury and death proliferate throughout the brain, connections between networks of neurons disintegrate and consequently die, affected regions begin to shrink in a process known as brain atrophy. Neuron death, particularly in the hippocampus, inhibits the patient’s ability to form new memories, thus contributing to the symptoms of the disease.
One specific process these molecules alter is Long-Term Potentiation (LTP), or the molecular mechanism by which memories are formed. Oligomers, or short polymers which contain fewer Aβ monomers than plaques, of Aβ have been shown to inhibit hippocampal LTP in vivo (Walsh et al., 2002, p. 535). While plaques were given significant attention in the past, researchers have recently begun to focus more closely on oligomers. As forgetfulness of new information is a key symptom in early Alzheimer’s disease, and the hippocampus is linked to the consolidation of memories, this study suggests that alterations of normal LTP is a key part of Alzheimer’s pathophysiology. Another, more recent study on human patients made similar discoveries: they found that LTP is abnormal in the cortex of Alzheimer’s patients (Di Lorenzo et al., 2016).
In addition to Aβ and Tau tangles, abnormal Acetylcholine neurotransmission is thought to play a key role in Alzheimer’s disease. One characteristic pathological feature of Alzheimer’s disease is the loss of neurons in the Nucleus Basalis of Meynert. As this nucleus is a key center for cholinergic neurons (neurons producing and transmitting Acetylcholine), this damage represents a key feature in the pathology of Alzheimer’s disease. Furthermore, the loss of neurons producing acetylcholine is linked to cognitive impairment in Alzheimer’s, but not necessarily its cause. It may be the case that Acetylcholine abnormalities and cognitive deficits are caused by another factor, or that the mechanism by which Acetylcholine is linked to the progression of Alzheimer’s disease is indirect. Because of this link between acetylcholine and Alzheimer’s disease, Cholinesterase inhibitors (inhibitors of the enzyme Acetylcholinesterase, which removes Acetylcholine from the synapse) are one class of medications used to treat Alzheimer’s disease (Francis, Palmer, Snape, & Wilcock, 1999).
Metals are also thought to play a role in the pathology of Alzheimer’s disease. Specifically, zinc and copper have been implicated in causing abnormalities in the activity of NMDA Glutamate receptors, known to play a critical role in Long-Term Potentiation, and thus memory as well. Furthermore, heightened iron content in certain tissues is also seen in the brains of Alzheimer’s patients (Barnham & Bush, 2011, p. 222).
While there is no current cure for Alzheimer’s disease, there are multiple drugs that have proven to slow disease progression and ameliorate symptoms. In order for specific symptoms to be treated, physicians categorize the symptoms into either “cognitive” or “behavioral and psychiatric.” Cognitive symptoms disrupt memory, language, judgment, and thought processes. Behavioral symptoms affect a patient’s actions and emotions (Alzheimer’s Association, n.d.).
Treatment for cognitive symptoms requires the alteration of chemical messengers in the brain. The U.S. Food and Drug Administration (FDA) has approved two types of medications to treat the cognitive symptoms of Alzheimer’s disease: cholinesterase inhibitors and memantine (Alzheimer’s Association, n.d.). The first type, currently approved for treating the symptoms of Alzheimer's disease in the early to moderate stages, blocks the enzyme responsible for the breakdown of Acetylcholine (ACh) in the brain. ACh is a salient neurotransmitter for learning and memory. Normal aging triggers a slight fall in the concentrations of ACh, causing periodic forgetfulness. However, in Alzheimer’s disease, the concentration of ACh is starkly diminished by about 90%, resulting in significant cognitive decline. The function of these drugs is to bolster communication among neurons by keeping ACh concentrations high. There are three cholinesterase inhibitors commonly prescribed for treating the cognitive symptoms of Alzheimer’s disease: Donepezil (approved to treat all stages), Rivastigmine (approved to treat mild to moderate stage patients), and Galantamine (approved to treat mild to moderate stage patients).
In addition to cholinesterase inhibitors, memantine is a drug approved by the FDA for treating the cognitive symptoms of Alzheimer's disease but for remedying the moderate to severe symptoms of Alzheimer’s disease. Memantine regulates the activity of the brain’s most abundant excitatory neurotransmitter, glutamate which is involved in learning and memory, by acting as a N-methyl-D-aspartate (NMDA) receptor antagonist. When glutamate binds to NMDA receptors to facilitate the flow of calcium in cells, glutamate can cause depolarization and increased intracellular Ca2+ ion concentration. A rising Ca2+ ion concentration in the cytoplasm prompts Ca2+ influx into mitochondria, in which mitochondrial Ca2+ accelerates and disrupts normal metabolism causing cell death (Gennady Ermak & Kelvin J.A Davies, 2002). Malfunctions in the action of the glutamate-glutamine cycle can spawn a “self-perpetuating neuronal death cascade” which may be the cause of the neurodegeneration seen in Alzheimer’s disease. Brain cells are over-excited to death by the pathophysiological action of glutamate in a process known as excitotoxicity (Heather Scott Walton & Peter R. Dodd, 2006). Memantine is a drug that aims to protect the nerves from the overstimulation of glutamate by blocking the NMDA receptors.
In addition to cognitive decline, Alzheimer's disease can cause grave behavioral and psychiatric symptoms. These symptoms include sleeplessness, agitation, hallucinations, and delusions (National Institute on Aging, 2015). There are two possible methods of treating the behavioral symptoms of Alzheimer’s disease: non-drug intervention and medication. Non-drug intervention approaches aim to alter the environment to eliminate obstacles and increase security. Another possibility is to investigate any potential conflicts or interactions between the patient’s medications that could cause adverse effects to behavior or psychiatric health. If these interventions fail to ameliorate the symptoms, introducing medication may help. Although the FDA has not specifically approved drugs to treat the behavioral and psychiatric symptoms of Alzheimer’s disease, physicians may consider practicing off label use of medications, that is, prescribing medications for a different purpose than what is it is approved. There are a multitude of medications that could be chosen depending on the symptoms. If the patient is experiencing depression, an antidepressant such as Prozac or Zoloft can be prescribed. Antipsychotics and anxiolytics may be prescribed to reduce hallucinations and anxiety, respectively (Alzheimer’s Association, n.d.).
Familial Alzheimer’s Disease - A form of Alzheimer’s disease linked to genetics
Sporadic Alzheimer’s Disease - A form of Alzheimer’s disease without a known genetic cause
Neurofibrillary Tangles - Pathological feature of Alzheimer’s disease caused by abnormal accumulation of Tau proteins, also known as Tau Tangles
Senile Plaques- Also called Amyloid-Beta (Aβ) Plaques, key pathological feature of Alzheimer’s disease
Neuritic Plaques - One subtype of senile plaques characterized by the presence of neurites and their spherical shape
Diffuse Plaques - Another subtype of senile plaques characterized by the absence of neurites and an amorphous shape
Long-Term Potentiation - The cellular process by which Glutamate neurotransmission alters synapses through the AMPA and NMDA glutamate receptors, and a subsequent signaling cascade
Oligomer - A short polymer
In vivo - In living organisms, contrast with in vitro (in test tubes, labs, etc.)
Nucleus Basalis of Meynert - A brain region highly implicated in Acetylcholine production and neurotransmission
Cholinesterase Inhibitors - A class of medications that target acetylcholinesterase (an enzyme that removes Acetylcholine from the synaptic cleft after signaling). Common types used to treat Alzheimer’s disease include Donepezil, Rivastigmine, and Galantamine
N-methyl-D-aspartate (NMDA) Receptor - A receptor for the neurotransmitter Glutamate that is implicated in learning through supporting Long-Term Potentiation
Non-drug intervention - A treatment of behavioral and psychiatric symptoms of Alzheimer’s disease involving altering the environment in which the patient lives
Cognitive Symptoms - Symptoms of Alzheimer’s disease involving cognitive functions, including memory, language, judgment, and thought processes
Behavioral and Psychotic Symptoms - Symptoms of Alzheimer’s disease affecting a patient’s emotions and actions
Memantine- A regulator of Glutamate used to treat moderate to severe symptoms of Alzheimer’s disease
Jacob Umans is an aspiring physician-scientist in the Stanford University Class of 2020. As a cofounder of the IYNA, he is passionate about science education and hopes to share his excitement about all subfields of neuroscience -- especially glial biology and neuroimmunity -- with students around the world. He hopes to go on to earn an MD/Ph.D. after graduating from Stanford and to use his clinical experience develop a research focused on developing a better understanding of and improved therapies for neurodegenerative diseases. Outside of neuroscience, Jacob is an avid fan of puns, table tennis, and reading.
My name is Brendan Mitchell, I recently graduated from the University of California, Riverside with a B.S. in Neuroscience. Since my first year at UCR, I worked in Dr. Xiaoping Hu's Bioengineering Lab. Since then, I’ve been privileged to receive research grants, publish my research as a primary author in a peer-reviewed journal, and present my work at UCR-hosted research symposiums. I recently submitted my Honors Capstone Thesis titled "Multimodal MRI Study using Convolutional Neural Networks for Schizophrenia Classification" for publication. And starting this fall, I will be working at the NIH via the IRTA Postbac Fellowship.