Lead Exposure & Alzheimer's Disease: Is There A Link?

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Lead Exposure & Alzheimers Disease: Is There A Link?
A factsheet for medical professionals
by Dr. Iman Hegazi, MBBS, MD. Forensic Medicine & Toxicology,
Global Lead Advice & Support Service (GLASS), run by The LEAD Group Inc
Alzheimer's disease (AD), or simply Alzheimer's, is the most common form of
dementia. This incurable, degenerative, and terminal disease was first described by German
psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him. (1)
Generally it is diagnosed in people over 65 years of age, although the less-prevalent early-
onset Alzheimer's can occur much earlier. An estimated 26.6 million people worldwide had
Alzheimer's in 2006; this number may quadruple by 2050. (2, 3)
The term "Alzheimer’s" is rapidly being used by the general public to refer to any
elderly person suffering from dementia. Everyone who suffers from Alzheimer's disease has
dementia. However, not everyone with dementia has Alzheimer's disease. Dementia may be
caused by several other diseases.
History:
Alzheimer’s disease, the chronic decline in intellectual capabilities, was recognized by
the ancient Greek physician Hippocrates. At the time "senility" was thought to be simply a
normal part of aging (4). Alois Alzheimer, better defined the disease in a speech given in
November 1906. Dr. Alzheimer examined the brain, after her death, of a woman who died
at the age of 56, after having paranoid delusions, hallucinations, and a loss of memory, and
noticed senile plaques and neurofibrillary tangles in the neurons (brain cells) (5). Alzheimer
wrote, "On the whole, it is evident that we are dealing with a peculiar, little known disease
process." Up until 1970 the diagnosis of Alzheimer’s disease was restricted to patients less
than 65 years old(4). Alzheimer’s disease is no longer defined by age with between 50% and
75% of all dementia cases now being diagnosed as Alzheimer’s disease, with the proportion
increasing with age (6,7).
Overview of Changes in the Brain:
Alois Alzheimer was able to describe two of the major changes in brain structure
caused by Alzheimer’s disease. In addition to the neurofibrillary tangles and neuritic
plagues, AD also results in granulovascular degeneration, brain shrinkage, and decreased
amounts of neurotransmitters (brain chemicals involved in communication). All of these
changes impair the function of brain cells (neurons) and eventually lead to cellular death.
Unlike many other cells, the brain is unable to regenerate new neurons. The gradual and
progressive death of neurons is mirrored in specific behaviour changes. (4)
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Phases of Alzheimer's
Mild dementia
The chief characteristic of mild Alzheimer’s disease is forgetfulness. Not only will the
individual misplace items but will start to place them in unusual locations (e.g. keys in the
freezer). The decline may be so gradual that it may take family members years to notice
since some forgetfulness is a natural part of aging. Loss of a sense of time and direction
greatly interferes with the ability to navigate and are important components of a "sense of
direction." The characteristic of becoming lost, especially in unfamiliar territory is a common
hallmark in mild AD. (4)
Moderate dementia
Once Alzheimer’s disease deteriorates to the moderate stage; profound memory loss that
interferes with daily activities characterizes the disorder. The AD patient in the moderate
stage is dependent upon others. The sufferer becomes lost even in familiar surroundings
and has lost the ability to learn any new material. (4)
Severe dementia
Once the disease progresses to the severe stage the patient suffers from severe impairment
of mind (cognitive functions) and body. The subject has reached the point they may no
longer recognize their spouse and children. The AD patient no longer has any sense of time
or current location. Verbal communication has decreased to the point of phrases, words, or
merely syllables are constantly repeated. Eventually, even this simple communication
degenerates to a complete inability to speak. The overall loss of coordination and body
control means the patient may require help dressing, bathing, grooming, eating, and
toileting. (4)

Description: Combination of two diagrams of the brain in one for comparison. Left: A normal brain.
Right: The brain of a person with Alzheimer's disease showing extreme shrinkage of the cerebral
cortex and hippocampus and enlargement of the ventricles. (8)
The copyright holder of this work grant anyone the right to use this work for any purpose , without any conditions,
unless such conditions are required by law. http://en.wikipedia.org/wiki/File:COMPARISONSLICE_HIGH.JPG
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Although Alzheimer’s disease (AD) is a progressive neurodegenerative disorder
whose clinical manifestations appear in old age, the initial events that trigger this disease
may begin very early in life.
In consequence of the “Barker hypothesis”, which links early life experiences and
adult diseases, there is a new concept regarding certain adult diseases that emphasizes the
role of environmental factors operating during the preconceptual, fetal, and infantile phases
of life. (9)
The sporadic nature of most AD cases strongly argues for an environmental link that
may accelerate normal age-related processes in the brain. Due to the widespread
occurrence of AD, such environmental agents (risk factors) would have to be widespread
and persistent, and chronic human exposure to them very common. Although few
environmental agents may fit this description, the heavy metal Pb is widespread and is
known to produce permanent behavioral and cognitive perturbations. (10, 11)
Lead (Pb) poses widespread public concern. Humans can be exposed to Pb through
paint, glazed earthenware, lead piping, solder in food containers, moonshine whiskey, and
automobile battery casings. Occupational exposure to Pb can come from smelters, battery
manufacturing, welding, automobile radiator repair, and production of Pb-based paints.
Although organic forms of Pb have been removed from gasoline, inorganic Pb still remains
the number one environmental hazard facing humans today. (12)
Occupational lead exposure may have long-term effects and dramatically increase
the risk of developing Alzheimer's disease in later years, according to research presented
during the American Academy of Neurology's 52nd Annual Meeting in San Diego, CA, April
29 -- May 6, 2000. Researchers believe that people who have worked in jobs with high levels
of lead exposure are up to 3.4 times more likely to develop Alzheimer's disease. Dr Koss of
the American Academy of Neurology quotes: "Although lead has long been known to be
toxic -- and is believed to have affected the brains of some of the rulers of the Roman
Empire, thereby causing its downfall -- its long-term damages are difficult to measure, and
thus, the extent of its negative effects have been largely overlooked." (13)
The pathogenesis of Alzheimer’s disease: Evidence for an environmental link:
AD pathology is characterized by senile plaques and neurofibrillary tangles (NFTs),
combined with massive neuronal loss. The major constituents of senile plaques (or amyloid
plaques) are 39–42 residue peptides (Aβ) snipped from a larger protein called the amyloid
precursor protein (APP). Current studies indicate that APP is processed by a group of
secretases. Cleavage of APP by β-secretase produces sAPPβ and C99 fragments. C99 is then
cleaved by γ-secretase to release Aβ. However, prior processing of APP by α-secretase
precludes the formation of the neurotoxic Aβ. Inhibiting α- secretase activity predisposes
the processing of APP via the β-secretase pathway, which ultimately leads to neurotoxicity.
On the other hand, suppression of β-secretase or γ-secretase activity prevents the
formation of the neurotoxic Aβ molecule. (14,15)
Aβ processing and aggregation are thought to be critical events in the etiology of
neurodegenerative diseases such as AD. Mutations in APP have been shown to promote AD
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pathogenesis in familial AD by altering its proteolytic processing, which results in an
increased production of Aβ. (16)
Recent studies in rodents have shown that exposure to lead (Pb) during brain
development predetermined the expression and regulation of the amyloid precursor protein
(APP) and its amyloidogenic β-amyloid (Aβ) product in old age. It is also reported that the
expression of AD-related genes [APP, BACE1] as well as their transcriptional regulator (Sp1)
were elevated in 23-year-old monkeys exposed to Pb as infants leading to an Alzheimer's
disease (AD)-like pathology in the aged monkeys. (17, 18)
Chronic lead (Pb) exposure also affected granule cell morphology in Pb-exposed rats.
Dendrites frequently appeared dystrophic, similar to those present in Alzheimer’s disease.
Dendrites play an essential role in neuronal signaling and aberrations in dendritic
morphology are likely to alter their functional characteristics. (19)
These data suggest that AD pathogenesis is influenced by early life exposures and
argue for both an environmental trigger and a developmental origin of AD. The findings
implicate an environmental agent (Pb) in the pathogenesis of AD and demonstrate that
development is an important period of vulnerability, which could increase future
susceptibility to neurodegeneration and AD pathology.
Therapeutic proof of heavy metal implication:
Clioquinol, a chelating agent used in heavy metal toxicity, is under investigation for
the treatment of Alzheimer disease. A pilot phase 2 study with clioquinol showed that the
effect of the treatment was significant in the more severely affected group and supports
further investigation of this novel treatment. Clioquinol is a chelator that crosses the blood-
brain barrier and may diminish the accumulation of amyloid beta in plaques. Clioquinol was
shown to produce a significant reversal of amyloid-beta plaque deposition in vitro as well as
in vivo in a clinical trial. (20, 21) Another pilot study has shown the efficacy of the chelating
agent d-penicillamine in reducing oxidative stress in Alzheimer disease patients. (22)
In conclusion, lead (Pb) is a xenobiotic metal with no known essential function in
cellular growth, proliferation, or signalling and there is compelling evidence that exposures
to Pb have adverse effects on the nervous system. (23) The sporadic nature of Alzheimer's
disease (AD) and a number of studies suggest that AD pathogenesis is influenced by early
life exposures and argue for both an environmental trigger and a developmental origin of
AD. Recent research presents novel findings that implicate lead (Pb) in the pathogenesis of
AD and demonstrate that development is an important period of vulnerability, which could
increase future susceptibility to neurodegeneration and AD pathology.

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