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Hello! I'm working on this article for a class project. I will be working on it until the end of April, 2015. Please do not edit or republish any of this information. Thank you.

Alzheimer's Disease

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Cause

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Genetics

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The genetic heritability of Alzheimer's disease (and memory components thereof), based on reviews of twin and family studies, range from 49% to 79%.[1][2] Around 0.1% of the cases are familial forms of autosomal (not sex-linked) dominant inheritance, which have an onset before age 65.[3] This form of the disease is known as early onset familial Alzheimer's disease. Most of autosomal dominant familial AD can be attributed to mutations in one of three genes: those encoding amyloid precursor protein (APP) and presenilins 1 and 2.[4] Most mutations in the APP and presenilin genes increase the production of a small protein called Aβ42, which is the main component of senile plaques.[5] Some of the mutations merely alter the ratio between Aβ42 and the other major forms—e.g., Aβ40—without increasing Aβ42 levels.[5][6] This suggests that presenilin mutations can cause disease even if they lower the total amount of Aβ produced and may point to other roles of presenilin or a role for alterations in the function of APP and/or its fragments other than Aβ. There exist variants of the APP gene which are protective.[7]

Most cases of Alzheimer's disease do not exhibit autosomal-dominant inheritance and are termed sporadic AD, in which environmental and genetic differences may act as risk factors. The best known genetic risk factor is the inheritance of the ε4 allele of the apolipoprotein E (APOE).[8][9] Between 40 and 80% of people with AD possess at least one APOEε4 allele.[9] The APOEε4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes.[3] Like many human diseases, environmental effects and genetic modifiers result in incomplete penetrance. For example, certain Nigerian populations do not show the relationship between dose of APOEε4 and incidence or age-of-onset for Alzheimer's disease seen in other human populations.[10][11] Early attempts to screen up to 400 candidate genes for association with late-onset sporadic AD (LOAD) resulted in a low yield,[3][4] More recent genome-wide association studies (GWAS) have found 19 areas in genes that appear to affect the risk.[12] These genes include: CASS4, CELF1, FERMT2, HLA-DRB5, INPP5D, MEF2C, NME8, PTK2B, SORL1, ZCWPW1, SlC24A4, CLU, PICALM, CR1, BIN1, MS4A, ABCA7, EPHA1, and CD2AP.[12]

Mutations in the TREM2 gene have been associated with a 3 to 5 times higher risk of developing Alzheimer's disease.[13][14] A suggested mechanism of action is that when TREM2 is mutated, white blood cells in the brain are no longer able to control the amount of beta amyloid present.

Cholinergic hypothesis

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Amyloid hypothesis

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In 1991, the amyloid hypothesis postulated that extracellular amyloid beta (Aβ) deposits are the fundamental cause of the disease.[15][16] Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit AD by 40 years of age.[17][18] Also, a specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. Whilst apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain.[19] Further evidence comes from the finding that transgenic mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer's-like brain pathology with spatial learning deficits.[20]

An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia.[21] Researchers have been led to suspect non-plaque Aβ oligomers (aggregates of many monomers) as the primary pathogenic form of Aβ. These toxic oligomers, also referred to as amyloid-derived diffusible ligands (ADDLs), bind to a surface receptor on neurons and change the structure of the synapse, thereby disrupting neuronal communication.[22] One receptor for Aβ oligomers may be the prion protein, the same protein that has been linked to mad cow disease and the related human condition, Creutzfeldt–Jakob disease, thus potentially linking the underlying mechanism of these neurodegenerative disorders with that of Alzheimer's disease.[23]

In 2009, this theory was updated, suggesting that a close relative of the beta-amyloid protein, and not necessarily the beta-amyloid itself, may be a major culprit in the disease. The theory holds that an amyloid-related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be triggered by ageing-related processes in later life to cause the neuronal withering of Alzheimer's disease.[24] N-APP, a fragment of APP from the peptide's N-terminus, is adjacent to beta-amyloid and is cleaved from APP by one of the same enzymes. N-APP triggers the self-destruct pathway by binding to a neuronal receptor called death receptor 6 (DR6, also known as TNFRSF21).[24] DR6 is highly expressed in the human brain regions most affected by Alzheimer's, so it is possible that the N-APP/DR6 pathway might be hijacked in the ageing brain to cause damage. In this model, beta-amyloid plays a complementary role, by depressing synaptic function.

Tau hypothesis

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In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells.

The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade.[16] In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies.[25] When this occurs, the microtubules disintegrate, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system.[26] This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.[27]

Sleep Disruption

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A more recent explanation of Alzheimer's pathology postulates that sleep disruption can lead to or exacerbate already existing Alzheimer's Disease. Around 40% of Alzheimer's patients suffer from sleep disruption and it is the most common cause of institutionalization.[28][29] In general, sleep fragmentation has been found to correlate with the incidence of the disease[30] and there are various explanations for this hypothesis.

Slow wave sleep (SWS) is an important part of Non-rapid eye movement sleep that is implicated in facilitating memory consolidation. The amount of SWS is correlated with next day memory recall in healthy and Alzheimer's disease patients.[31] During SWS, mammals express two well defined oscillatory patterns, hippocampal ripples and cortical spindles. In Alzheimer's disease, patients show a decrease in time spent in SWS and a decreased ratio of SWS to REM sleep. Patients also show a reduction in fast spindles and overall spindle density, two measures which are associated with accuracy on memory recall tasks.[32] A reduction of SWS may lead to a breakdown of memory consolidation between the hippocampus and neocortex.[33]

Sleep disruption also adds a new dimension to the Amyloid hypothesis. In healthy patients, Aβ levels increase with wakefulness, but decrease during rest. In patients with Alzheimer's disease, there is less variability in Aβ, which remains high at night. This correlates with sleep disruption and increased wakefulness, which may lead to an overall increase in Aβ production.[34] Sleep disruption, therefore, could contribute to the build of Aβ proposed by the Amyloid hypothesis.

Another possible cause of sleep disruption is deregulation of hypocretin, melanin-concentrating hormone (MCH) and melatonin, three neuropeptides important in sleep and wakefulness. A deficiency in hypocretin is associated with sleeping disorders such as narcolepsy. Patients with Alzheimer's have decreased levels of hypocretin and hypocretin-1 neurons.[35] Low levels of hypocretin-1 has also been shown to correlate with increased sleep fragmentation in Alzheimer's.[36] If hypocretin levels are deregulated in Alzheimer's disease, then this could lead to poor sleep quality and therefore increased memory impairment.

MCH is correlated with Aβ levels and tau proteins associated with Alzheimer's. The levels of MCH in cerebral spinal fluid negatively correlate with memory. It has been suggested that misfolded tau protein tangles result in the hypersecretion of MCH, leading to daytime sleepiness and memory impairment.[37]

A potential treatment for Alzheimer's disease currently being tested is prolonged-release melatonin supplements. Melatonin improved sleep in Alzheimer's patients with and without insomnia, and it not only stopped memory decline, but improved performance after only 12 weeks. [38]

Other hypotheses

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Sleep and Memory

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Methods of measuring memory

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Behavioral measures

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  • A self-ordered pointing task is a task of memory where a participant is presented with a number of images (or words) which are arranged on a display. Several trials are presented, each with a different arrangement and containing some of the previous words or images. The task for the participant is to point to a word or image they had not previously pointed to in other trials.[39]
  • In a recency discrimination task participants are shown two trials of image presentation and then a third trial containing a mixture of images from the first and second trial. Their task is to determine whether the image was from the most recent presentation or the previous one.[39]
  • In a route retrieval task spatial learning occurs where a participant virtual tours a particular place (such as a town or maze). Participants are asked to virtually tour the same thing at a later time while brain imaging is used to measure activity.[40]
  • A paired word associative task consists of two phases. During the first phase (acquisition), the responses of the paired-associate task are learned and become recallable. In the second phase (associative phase), the subject learns to pair each response to a separate stimulus. For example a visual cue would provide information as to what words must be recalled after the stimulus and words are removed.[41]
  • In a mirror tracing task participants are asked to trace several figures as fast and as accurately as possible which they can only see in a mirror. Speed is recorded as well as how much they deviate from the original image (accuracy).[41]
  • In the Morris water maze task rats are used to test their spatial learning in two kinds of conditions: spatial and nonspatial. In the spatial condition, a platform is hidden by using murky water and in the nonspatial condition, the platform is visible. The spatial condition the rat must rely on their spatial memory to find the platform whereas the nonspatial condition is used for comparison purposes.[42]
A rat undergoing a Morris water navigation test
  • The serial reaction time task (SRT task) is a task whereby subjects face a computer screen where several markers are displayed that are spatially related to relevant markers on their keyboard. The subjects are asked to react as fast and accurately as possible to the appearance of a stimulus below one of the markers. Subjects can be trained on the task with either explicit instructions (e.g. there are colour sequences presented which must be learned) or implicit ones (e.g. the experimentor does not mention colour sequences, thus leaving the subjects to believe that they are taking place in a speed test). When this task is used in sleep studies, after a time delay, subjects are tested for retention.[43]
  • In a block tapping task participants are asked to type a sequence of five numbers with their dominant or non-dominant hand (specified in experiment), for an allotted period of time, followed by a rest period. A number of these trials occur and the computer records the number of sequences completed to assess speed and the error rate to assess accuracy.[44]
  • A finger tapping test is commonly used when a pure motor task is needed. A finger tapping test requires subjects to continuously press four keys (typically numerical keys) on a keypad with their nondominant hand in a sequence, such as 4-3-1-2-4, for a given amount of time. Testing is done by determining the number of errors made.[45]

Neural imaging measures

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Neuroimaging can be classified into two categories, both used in varying situations depending on what type of information is needed. Structural imaging deals predominately with the structure of the brain (computed tomography) while functional imaging deals more heavily with metabolic processes in regards to anatomical functioning (positron emission tomography, functional magnetic resonance imaging). In recent years, the relationship between sleep and memory processes had been aided by the development of such neuroimaging techniques.[46]

Positron emission tomography (PET) is used in viewing a functional processes of the brain (or other body parts). A Positron-emitting radionuclide is injected into the blood stream and emits gamma rays which are detected by an imaging scanner. Computer analysis then allows for a 3-dimensional reconstruction of the brain region or body part of interest.

Functional magnetic resonance imaging (fMRI) is a type of brain imaging that measures the change of oxygen in the blood due to the activity of neurons. The resulting data can be visualized as a picture of the brain with colored representations of activation.

Molecular measures

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Although this may be seen as similar to neuroimaging techniques, molecular measures help to enhance areas of activation that would otherwise be indecipherable to neuroimaging. One such technique that aids in both the temporal and visual resolution of fMRI is the blood-oxygen-level dependent (BOLD) response. Changes in the BOLD response can be seen when there is differing levels of activation in suspected areas of functioning. Energy is supplied to the brain in the form glucose and oxygen (which is transferred by hemoglobin). The blood supply is consistently regulated so that areas of activation receive higher amounts of energy compared to areas that are less activated.[47] In positron emission tomography, the use of radionuclides (isotopes with short half lives) facilitates visual resolution. These radionuclides are attached to glucose, water and ammonia so that easy absorption into the activated brain areas is accomplished. Once these radioactive tracers are injected into the bloodstream, the efficiency and location of chemical processes can be observed using PET.[48]

Methods of measuring sleep

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Electrophysiological measures

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The main method of measuring sleep in humans is polysomnography (PSG). For this method, participants often must come into a lab where researchers can use PSG to measure things such as total sleep time, sleep efficiency, wake after sleep onset, and sleep fragmentation. PSG can monitor various body functions including brain activity (electroencephalography), eye movement (electrooculography), muscle movement (electromyography), and heart rhythm (electrocardiography).

Electroencephalography (EEG) is a procedure that records electrical activity along the scalp. This procedure cannot record activity from individual neurons, but instead measures the overall average electrical activity in the brain.

Electrooculography (EOG) measures the difference in electrical potential between the front and the back of the eye. This does not measure a response to individual visual stimuli, but instead measures general eye movement.

Electromyography (EMG) is used to records the electrical activity of skeletal muscles. A device called an electromyograph measures the electrical potential of muscle cells to monitor muscle movement.

Electrocardiography (ECG or EKG) measures the electrical depolarization of the heart muscles using various electrodes placed near the chest and limbs. This measure of depolarization can be used to monitor heart rhythm.

Behavioural measures

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Actigraphy is a common and minimally invasive way to measure sleep architecture. Actigraphy has only one method of recording, movement. This movement can be analyzed using different actigraphic programs. As such, an actigraph can often be worn similarly to a watch, or around the waist as a belt. Because it is minimally invase and relatively inexpensive, this method allows for recordings outside of a lab setting and for many days at a time. But, actigraphy often over estimates sleep time (de Souza 2003 and Kanady 2011).

Alternative sleep schedules

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Sleep and Aging

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Sleep often becomes deregulated in the elderly and can lead to or exacerbate preexisting memory decline.

Healthy older adults

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The positive correlation between sleep and memory breaks down with aging. In general, older adults suffer from decreased sleep efficiency.[49] The amount of time and density of REM sleep and SWS decreases with age.[50][51][52] Consequently, it is common that the elderly receive no increase in memory after a period of rest.[53]

To combat this, donepezil has been tested in healthy elderly patients where it was shown to increase time spent in REM sleep and improve next day memory recall.[54]

Alzheimer's disease

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Main article: Alzheimer's disease

Patients with Alzheimer's disease experience more sleep disruption than the healthy elderly. Studies have shown that in patients with Alzheimer's disease, there is a decrease in fast spindles. It has also been reported that spindle density the night before a memory test correlate positively with accuracy on an immediate recall task.[50] A positive correlation between time spent in SWS and next day autobiographical memory recall has also been reported in Alzheimer's patients.[55]

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