Running head: ALZHEIMER’S DISEASE: THE THIEF OF THE MIND
Alzheimer’s Disease: The Thief of the Mind
Diana M. Wright
California State University, San Bernardino
Alzheimer’s Disease (AD) is a growing concern for everyone in our society. AD is the leading form of dementia, and is responsible for 50% to 60% of dementia (Blennow et al, 2006). Less than 1% of seniors between the ages 60 and 64 are afflicted with AD; however, 24% to 33% of seniors over 85 years of age are afflicted (Blennow et al, 2006). Clearly, every person who reaches his or her golden years does not develop AD. Interestingly, about 10% of those afflicted with AD exhibited symptoms before reaching fifty years of age (Kandel et al, 2000). This early onset form of AD, although rare, is prevalent in some families with a history of the disease (Kandel et al, 2000). It is not currently possible to determine if a person will develop AD as the cause of the disease is based only on theory. In fact, the only conclusive way to determine AD is by autopsy (Fagan et al, 2005). It can be very difficult to differentiate AD from other forms of dementia (Blennow et al, 2006). Studies of the cause of early onset AD has shed some light on the genetic link, and in conjunction with research of later onset AD could eventually enable better detection and treatment.
A glycoprotein called apolipoprotein E (ApoE) which carries lipids, including cholesterol, has been found to increase the risk of AD (Kandel et al, 2000). An allele is an alternate form of a gene that is responsible for varying traits. There are actually three alleles: ApoE2, ApoE3, and ApoE4 at the ApoE locus (Kandel et al, 2000). Presence of the ApoE4 gene increases the risk of developing AD (Mosconi et al, 2005). The presence of the ApoE4 allele will cause an earlier and faster progression of AD otherwise known as early onset AD (Mosconi et al, 2005). The ApoE gene is related to the reparative cellular mechanisms which it inhibits, but ApoE4 is the most offensive (Mosconi et al, 2005). Essentially, the ApoE4 gene is believed to facilitate brain damage through synapse loss (Mosconi et al, 2005). The process of damage to the brain can occur for one to two decades before the earliest symptoms of AD are obvious (Fagan et al, 2005). The reason this damage can occur to the brain without any immediate effect is because of a brain reserve (Mosconi et al, 2005). The buildup of amyloid-$ (A$) in plaque is evidence that AD is the destruction of neural cells (Fagan et al, 2005). A$ is a protein that is produced by the degeneration of brain tissue. The exact process by which the ApoE4 gene effects the loss of brain cells is theoretical.
The huge presence of amyloid-$ is a pathological indication of AD. While it might seem that the huge presence of amyloid-$ is a mere by product of neural cell destruction it is actually part of the cause. The ApoE4 gene somehow causes the huge presence of amyloid-$. The over abundance of amyloid-$ facilitates the formation of neurofibrillary tangles (NFT) of tau protein (Stahl, 2000). Neurofibrillary tangles are strands of tau protein that have been chemically changed, and wrapped together like two strands of rope (Stahl, 2000). The presense of NFT impairs the transmission of molecules in the axon of these neurons (Stahl, 2000). Essentially, NFT prevents neurons from transmitting nerve impulses. An unnecessarily large number of neurons are present in the beginning, and are decreased in a natural developmental process because of the lack of electrical nerve impulses or more directly, “use it or loose it” (Nelson, 2005). In effect, AD causes the same kind of elimination of neurons, but not from lack of use; rather, the affected neurons are inhibited or prevented from being used by NFT. In theory, the accumulation of amyloid-$ causes the death of neurons similar to how the accumulation of excessive cholesterol causes coronary artery disease; AD could be the result of either an overabundance of amyloid-$ or an inherent inability to dispose of it (Stahl, 2000).
Amyloid-$ is created from altered Amloid Precurser Protein (APP) due to abnormal DNA (Stahl, 2000). APP is considered to be connected with creating and preserving of neural synapses (Small et al, 1999). An increase of normal APP is noticed during the development of the spinal cord, but declines following development, which implies that APP is more essential for the generation of neural synapses than the maintenance of previously formed neural synapses (Small et al, 1999). While normal APP is readily removed from the neuron, the altered APP stays in the neuron and produces amyloid-$ which has the opposite effect of normal APP of causing the destruction of neurons (Stahl et al, 1999). Alternately, it is possible that there is an APO-E protein that would normally attach to amyloid to facilitate their removal is defective thus, enabling amyloid-$ to facilitate the destruction of neural cells. This is based on the theory of the Amyloid Cascade Hypothesis whereby increased amyloid-$ due to mutation causes oxidative stress to cells causing destruction (Lee et al, 2006).
While much of the Amyloid Cascade Hypothesis is based on experiments in which amyloid-$ causes oxidative stress, it has also been found that oxidative stress can cause increased production of amyloid-$ (Lee et al, 2006). Based on this concept and additional research, Lee et al (2006) submit that the genetic defect which causes AD creates oxidative stress that essentially causes the destruction of neural cells while also causing the production of amyloid-$. Lee et al (2006) maintains that their Alternate Amyloid Hypothesis is as viable as the Amyloid Cascade Hypothesis. People with Down syndrome inevitably develop AD by the age of 50 years because they formulate excessive amyloid-$ prior to adulthood and as soon as 12 years of age, which is long before the formulation of NFT (Lee et al, 2006). In effect, the Alternate Amyloid Hypotheis cites the abundance of amyloid-$ as a side effect of AD rather than a cause. Further, the research Lee et al (2006) suggest that amyloid-$ is not a toxic agent but could be associated with the decrease of oxidative damage. In fact treating AD afflicted patients with anti- amyloid-$ antibodies invariably kills cells; thus, amyloid-$ seems to be important in the preservation of neural cells.
Amyloid Cascade Hypothesis maintains the production of amyloid-$ causes the oxidation of neural cells in AD; yet, Alternate Amyloid Hypothesis maintains the opposite ideas that neural cell oxidation causes the production of amyloid-$ (Hardy, 2006). It is entirely plausible that the increased production of amyloid-$ is a defensive or protective response to neural cell damage (Hardy, 2006). Regardless amyloid-$ production is protective or adaptive, it can be very harmful. It could be loosely compared to the body’s production of antihistamines in reaction to allergies. More precisely, a normally defensive reaction in over production of amyloid-$can have an opposite and devastating effect. Of course, the greatest source of support for the Alternate Amyloid Hypothesis is the inevitable development of persons with Down syndrome of early onset AD that could be due to some other defective gene (Hardy, 2006). It may be erroneous to correlate findings from Down syndrome persons who are trisomic (have and extra chromosome) considering that the pathology of AD is not found in them. Nonetheless, amyloid-$ is an integral part of the pathology of AD and is either a major indication or contributor to its onset. It should be noted that with the exception of the presence ApoE4 or early onset AD, persons with the ApoE locus will not necessarily develop AD, which most certainly differentiates conventional AD to, that experienced by AD experienced by persons with Down syndrome.
Multiple experimentation has determined that normal neural circuit activity preserves neurons from being deleted in through normal development (Nelson, 2005). Persons with Down syndrome are far from normal development. Persons with Down syndrome lack cognitive skills and brain activity by virtue of their genetic disorder. Lowered brain activity may cause the omission of neural cells in Down syndrome patients because of the natural “use it or loose it” selection of neural electrical activity. Essentially, AD in persons with Down syndrome may be a form unique to their genetic disorder and should not be used as a model to study a postulate from. Additionally, the measurement of cognitive function is used to determine the progression of AD (Wilson, 2006). Considering that the cognitive function of persons with Down syndrome is inherently low to start with, the respective measurement of their cognition would be less a measurement of the progression of AD and more a measurement of the trisomic condition. Furthermore, the destruction of neural cells is not widespread throughout the brain.
The destruction of neural cells is specific to the temporal, prefrontal and perietal portions of the brain with the remainder of the brain including the basil ganglia, thalamus and brainstem that handle the senses and motor control being essentially unharmed (Sun & Alkon, 2004). As would be expected, the portions of the brain most affected by AD are responsible for memory and cognition. Additionally, these portions of the brain work together to formulate language. Although it is still unclear why AD specifically attacks these portions of the brain, a relationship between language ability and AD has been found. The Nun Study revealed that the lack of language ability in young adulthood can be a precursor to the development of AD as a senior, and the exact deficit of language ability can correlate to the severity of AD (Riley, 2005). It has frequently been postulated that actively exercising the mind with puzzles or cognitive exercises can potentially fend off AD.
Aside from exercising the brain, there may be other ways to fend against AD. Previously, an analogy was offered relating the production of amyloid-$ to cholesterol. Interestingly, a more direct link between cholesterol and AD had been found through the production of amyloid-$ via APP (Reiss, 2005). High cholesterol causes greater production of amyloid-$ which has been linked to the development of AD (Reiss, 2005). Additionally, ApoE determines how cholesterol is carried in the Central Nervous System (Reiss, 2005). As a result, heightened levels of cholesterol could be an autonomous contributing factor in the development of AD (Reiss, 2005). In addition to prevent coronary artery disease, maintaining a healthy level of cholesterol could also decrease the chance of developing AD. If the link between cholesterol and AD is strong as it appears than links between disease caused by high cholesterol and AD may also be evident.
The possible connection between high cholesterol and AD was investigated in the interest of providing an association of atherosclerotic hear disease (ASHD) and the potential to develop AD which yielded proposition that the level of lipids can foretell AD (Yaffe et al, 2002). Moderate decreases in cognition were even found to be associated with lipid levels. When total cholesterol (TC) and low density lipoprotein (LDL) were lowered over a period of four years it translated into a decrease of 50% risk of the decrease of cognition irrespective of ApoE4 presence (Yaffe et al, 2002). It is not extremely surprising that cholesterol can lead to health problems including AD, but there may even be specific elements in foods that can affect the development of AD. The destruction of neural cells resulting from excessive calcium intake has been a topic of study for at least fifty years (Canzoniero & Snider, 2005). The effect of excessive calcium on AD is not as great as it is on stroke; however, when amyloid-$ and high calcium act together the effect was increased destruction of neural cells (Canzoniero& Snider, 2005). Interestingly, the connection between calcium and AD is also linked to extremely low calcium levels which can also destroy neural cells (Canzoniero & Snider, 2005).
Other elements like calcium have been found to linked with neurological disorders or more specifically, developmental disorders. Specifically, certain metals have a long relationship between the contact of lead and children with retardation as well as with mercury. Ingestion of high levels of aluminum can increase amyloid-$ production (Becaria et al, 2003). The effect on the development of AD would be more pronounced where there are already high levels of amyloid-$ (Becaria et al, 2003). These findings are consistent with the previously discussed relationship between calcium and amyloid-$. The ingestion of high levels of copper was also examined but did not exemplify as significant results as that of aluminum (Becaria et al, 2003). Furthermore, aluminum is a metal that is not only present in the brain but increases in amount with age (Becaria et al, 2003). The correlation between increased levels of aluminum in the brain with age and its connection with AD are not entirely clear (Becarira et al, 2003). However, it draws into question if the increase of incident of AD with age may be directly related to a factor resulting from age like increased aluminum in the brain rather than age alone. While it may be possible to avoid ingestion of aluminum, prevention will only aid the next generation; however, treatment is a current concern.
There are some therapeutic treatments currently being explored for the treatment of AD or at least the decrease in progression of the disease including drugs to protect neurons, metal blocking compounds, vaccines and stem cell implantation (Greenberg & Jin, 2006). Considering that stem cells can adapt themselves to the formation of any type of cell without the likelihood of developing immune reactions, they are potentially effective treatment for AD but due to the current restrictions are not very practical (Greenberg & Jin, 2006). Amazingly, the brain may actually have an inherent way to regenerate or actually produce new cells. There is a process in which neural cells made from previously indeterminate neural cells called neurogenesis (Greenberg & Jin, 2006). The process of neurogenesis occurs naturally in the brain following a brain injury including stroke as well as physical trauma and has even been observed in cases of AD although it may have been attributed to conventional treatments like drug therapy (Greenberg & Jin, 2006). The exact mechanism that triggers neurogenesis is not entirely clear but does not appear to require the death of neurons, and seems to be triggered by a combinations of the loss of synapse transmission (Greenberg & Jin, 2006). It is possible the toxicity of APP via amyloid-$ may be impairing the full effect of neurogenesis in person afflicted with AD (Greenberg & Jin, 2006). If the specific relationship between APP, amyloid-$ and AD can be unlocked it may be possible for the brain to repair itself through neurogenesis.
It was not long ago that AD was unceremoniously included in with all other types of dementia as if it were a mental disorder. Fortunately, the collection of statistical information as well as education has changed these misconceptions. Accounting for 50% to 60% of all forms of dementia, it is clearly the most common (Blennow et al, 2006). 24 million persons were afflicted with dementia as of 2001; this has been predicted to double in twenty year increments because of increasing life spans eventually reaching as many as 81 million by the year 2040 (Blennow et al, 2006). Unfortunately, the only way effectively diagnosis for AD is through autopsy following an afflicted person’s death (Fagan et al, 2005). While debate continues in the medical community of the exact process by which AD infiltrates the brain, a definite genetic link of APP and the production of amyloid-$ had been indicated. While the exact function of normal APP as well as amyloid-$ is unclear, it is promising that the answer to these question may also enable the most promising cure of neurogenesis.
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Alzheimer's is a very hard disease to see a loved one go through. My sweet grandmother had Alzheimer's, but thankfully it did not take over her whole mind like it does to many people. I miss and love you very much Grandma Rest In Peace.
