Anthony Murphy

Unit 2 Final Draft 3/17/2015

Dr Cecelia Musselman ENGW3307
CSE Style Citations
Word Count: 2006

The Complex Relationship of Alzheimers and Circadian Rhythmicity

Abstract
Circadian rhythms are 24 hour cycles which dictate when physiological functions occur during
the day, often through hormone excretion. Disrupted rhythms, such as those caused by night shift work,
have been associated with increased rates of preterm births, heart attacks, transient ischemic attacks,
strokes, and cancer. Alzheimers Disease is a neurodegenerative disease which causes dementia and
severe amnesia and is associated with disrupted circadian oscillators. Research has shown that the
disrupted rhythms contribute heavily to disease progression; it has been hypothesized that regulation of
these rhythms through manipulation of zeitgebers may have beneficial effects. By exposing patients to
regular light cycles, sleeping schedules, and eating schedules, patients could lessen symptoms and
potentially slow progression of Alzheimers.

Introduction
Dementia is an extremely costly disease state. In 2010, the world-wide annual cost of dementia
was estimated to be around $604 billion dollars from direct medical care costs such as drugs and hospital
care, social care costs such as support programs, and indirect costs 3 . Indirect costs, such as basic living
costs for a person who cannot work due to dementia, are typically paid by friends and family4 . The
biggest cause of dementia, other than the onset of dementia from old age, is Alzheimers disease.
Although a cure for dementia is likely a long way off 3 , it may be possible to reduce its prevalence by
aiding patients with Alzheimers. New research into Alzheimers and its relationship with circadian

rhythms could open up new methods of treating Alzheimers symptoms and slowing its progression by
trying to manipulate said rhythms4 .

Alzheimers Disease background

Alzheimers Disease (AD) is a neurodegenerative disease affecting over 5 million people
in the United States as the 6th leading cause of death8 . It causes severe amnesia and is the most common
cause of dementia worldwide. As with many other neurological disorders, Alzheimers disease is
associated with dysfunctional circadian rhythms. AD is an age-related disease with a very slow
progression; studies have shown that there are changes in biochemical markers in the cerebrospinal fluid
of some patients up to 25 years before symptoms show1 . There is currently no known cure for AD.
AD is associated with the accumulation of Amyloid- in the brain5 . Neurons produce a protein
called amyloid precursor protein, which is cut by enzymes into peptides called Amyloid-s. Amyloid-
forms insoluble plaques in the brain, which is associated with synaptic dysfunction and neuronal loss 5 .
Amyloid-imaging has shown that Amyloid- starts accumulating before symptoms of Alzheimers start
showing; this period of the disease is termed preclinical Alzheimers disease 5 . In healthy patients,
Amyloid- concentrations follow a cyclic pattern that rises in wakeful hours and decreases during sleep 2,5 .
Alzheimers also has profound effects on the rhythmicity of thyroid stimulating hormone (TSH).
TSH is produced by the pituitary gland and causes the thyroid to start producing hormones such as TH3
and TH4 that help regulate metabolism. TSH levels in Alzheimers patients have been shown to not only
lose their rhythmicity, but also lower overall1 . Thyroxin, which regulates TSH expression, was also
shown to be present in reduced levels 1 . Low TSH levels are associated with cognitive impairment and
dementia1 .

Circadian Rhythms Background

Circadian rhythms are cycles which dictate when physiological functions occur during the day.
Although their exact molecular mechanisms are not fully understood, these biological clocks are found in
many tissues in the body, such as liver, kidney, lung, brain, and adipose tissue6 . The clocks in these
tissues are used to control the timing of processes such as GI tract motility, gene expression, hormone
secretion, renal function, and cycles in body temperature and metabolism. To ensure that all of the
individual physiological cycles of the body occur in time with each other, these peripheral oscillators
must be synchronized. The many peripheral clocks of the body are entrained by hormonal and neuronal
cues from the master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus6 .
The SCN has an endogenous period of about 24 hours, varying with the individual but typically
slightly longer, and needs inputs from the environment, called zeitgebers, to match the 24 hour day. The
primary zeitgebers of the SCN are light-dark cycles. As the SCN is located in the hypothalamus it borders
the optic chiasm, and is entrained directly by photoreceptive ganglion cells 1 . Without entrainment by light
cycles, the rhythms will not be lost completely due to the endogenous period of the clock, but will
continually shift as the period is not exactly 24 hours. By synchronizing oscillators in the body based on
light cycles, the SCN directly synchronizes physiological processes to environmental cycles 2,6 . In other
words, the body can dictate which processes happen at which point in the day based on when the subject
is seeing light. In the absence of light cycles, such as in blind individuals, feeding has been shown to act
as the dominant zeitgeber3 .

Dysfunctional Biological Clocks and Hormone Effects

Circadian oscillators are found in many tissues of the body and help to regulate many types of
hormone expression; figure 1 provides a brief summary of a handful of compounds regulated. One of the
most robust rhythms in hormone levels is seen in melatonin. Melatonin secretion is dependent on the

light/dark cycle, and it has been shown to regulate gene expression within the SCN 3,6 . However,
pinealectomy does not prevent circadian rhythmicity, showing that the SCN can function somewhat
without melatonin3 . As an antioxidant, melatonin helps to remove free oxygen radicals and nitrogen
oxide, causing health risks in patients with dysfunctional circadian rhythms 3 . Because melatonin is
responsible for allowing the body to sleep, disrupted circadian rhythmicity is always associated with
disrupted sleep cycles, causing repeated awakening at night7 .
Glucocorticoid, a stress hormone, is regulated by the hypothalamic-pituitary-adrenal axis (HPA
axis), and normally exhibits consistent daily patterns of expression. However, chronic activation of the
HPA axis can lead to increased glucocorticoid sensitivity, causing higher levels of glucocorticoid 6 . As
the oscillators in the adrenal gland act as a gate for signaling glucocorticoid, circadian rhythm dysfunction
can lead to this phenomenon. Higher glucocorticoid levels have been associated with depression and
deficits in the functioning of brain and reproductive tissues 6 .
Functioning of oscillators in the liver and adipose tissue are associated with health risks, as well.
Abnormal clock gene (CG) expression in these tissues lead to different feeding patterns, hepatic
responses, and glucose/insulin metabolism6, 7 . As feeding behavior is modulated by a complex series of
feedback loops which involve many different biochemical, it is postulated that disruption of these signals
may also cause changes in feeding preferences. These kind of changes in feeding behavior are associated
with metabolic diseases such as obesity and diabetes 6 .
Through studying night-shift workers, other health risks have been associated with the external
manipulation of circadian rhythms. Shift work has been associated with reproductive issues, such as
increased rates of preterm births and lower birth-weights, as well as cancer of the breast, prostate, and
gonads7 . An increased rate of adverse cardiovascular function has also been observed, such as heart
attacks, transient ischemic attack, and stroke 6,7 . An overall lowered immune function as also been
observed as well as a generally higher mortality7 .

Manipulating Circadian Rhythms to Mediate Alzheimers Symptoms

Disrupted circadian rhythms are responsible for the existence or worsening of many Alzheimers
symptoms; and although no drugs or treatments have been identified to treat Alzheimers disease directly,
relief from some symptoms may be achieved through regulation of circadian rhythms. Although sleep
disruption is a result of Alzheimers, research suggests that it may also contribute heavily to the disease
progression2,7 . Researchers postulate that by helping patients regain some of the lost sleep, they may
relieve symptoms and possibly slow the progression of Alzheimers 2 . Helping a patient gain good sleep
hygiene by resisting naps in the day and going to sleep at a regular time may help somewhat, and it is also
theorized that using bright light to try and synchronize circadian rhythms through phase shifts may help
dysfunctional circadian rhythms as well2 .
However, disrupted circadian rhythms may not only be due to problems in the central clock in the
SCN, but could also be due to a hindered communication between the SCN and peripheral clocks. This
leads researchers to think that the use of another zeitgeber, food, is possible and could be used to alleviate
symptoms of Alzheimers4 . Ghrelin is a hormone synthesized by oxyntic cells in the stomach and by
neurons in the hypothalamic nuclei. It acts in the pituitary to stimulate energy homeostasis, cortisol
release, appetite, and weight gain, and is seen to rise just prior to eating4 . Although it is not thought to be
the food-entrainable oscillator, it acts downstream from the oscillator and help entrain clocks and
strengthen the zeitgeber4,6 . Therefore, administering Ghrelin to patients daily could help amplify the
effects of food-entrainment to scheduled daily meals, therefore somewhat restoring circadian rhythmicity
and benefitting Alzheimers patients.

Conclusion
Disrupted circadian rhythms are often seen as merely a side effect of Alzheimers disease, one of
many life-changing disabilities caused by the slow degeneration of the brain. However, it is very
important that its significance to the disease not be overlooked. Not only is it a symptom of the, but it is a
contributor to the disease. With this knowledge, safe, easy, and cheap treatment could be offered to all
Alzheimers patients; treatment as simple as a rigid schedule for sleep and meals could be easily be given
to the caretaker of the patient without the need of a medical professional. With continued research into
these simple manipulations of endogenous rhythmicity, the lives of millions of patients could be
improved.

Name of
protein/hormone
Amyloid-

Healthy

Alzheimers

Rises in the day

and falls at night

Accumulates onto
extracellular
plaques in the
brain.

TSH

TSH levels
follow daily
cyclic patterns

Always low, no
cycles

Melatonin

Melatonin levels
follow daily
cyclic patterns

Glucocorticoids

Relatively low
levels unless
under stress

Abnormal
melatonin
secretion, not as
cyclic
Heightened levels

Purpose of
hormone/protein
Function not
well understood,
has antimicrobial and
proinflammatory
properties.
Thyroid
Stimulating
Hormone
controls
metabolism.
Melatonin helps
one fall asleep
and stay asleep.
Helps lower
inflammation
and increases
and maintains
glucose levels.

Disease Effect
Accumulation in
the brain leads to
inflammation and
increased
resistance to
insulin, impairing
glucose
utilization..
Lowered
metabolism.

Sporadic sleep
patterns, wakeful
nights.
High levels
associated with
depression

Figure 1: The functions of three hormones, thyroid stimulating hormone, melatonin, and
glucocorticoids, and the function of the peptide Amyloid . The changes of expression in Alzheimers
patients is included along with the physiological effect of said change.

Literature Cited

1. Chen JM, Huan CQ, Ai Ming, KL. 2013. Circadian rhythm of TSH levels in subjects with
Alzheimers disease (AD). Aging Clin Exp Res 25:153-157.

2. Figueiro MG, Plitnick BA, Lok A, Jones GE, Higgins P, Hornick TR, Rea MS. September 2014.
Tailored lighting intervention improves measures of sleep, depression and agitation in persons
with Alzheimers disease and related dementia living in long-term care facilities. Clinical
Interventions in Aging.

3. Jenwitheesuk A, Nopparat C, Mukda S, Wongchitrat P, Govitrapong P. 2014 Melatonin

Regulates Aging and Neurodegeneration through Energy Metabolism, Epigenetics, Autophagy
and Circadian Rhythm Pathways. International Journal of Molecular Sciences 15:16848-16884.

4. Kent BA. September 2014. Synchronizing an aging brain: can entraining circadian clocks by food
slow Alzheimers disease? Frontiers in Aging Neuroscience.

5. Lucey BP, Bateman RJ. March 2014 Amyloid-B diurnal pattern: possible role of sleep in
Alzheimers disease pathogenesis. Neurobiology of Aging 35:529-534.

6. Oritz-Tuldela E, Martinez-Nicolas A, Diaz-Mardomingo C, Garcia-Herranz S, Pereda-Perez I,

Valencia A, Peraita H, Venero C, Madrid J, Rol M. 2014. The Characterization of Biological
Rhythms in Mild Cognitive Impairment. BioMed Research International.

7. Zelinski EL, Deibel SH, McDonald RJ. 2014. The trouble with circadian clock dysfunction:
Multiple deleterious effects on the brain and body. Neuroscience and Biobehaviorial Reviews
40:80-101.

Acknowledgements
The tireless Maria Albrecht, for proof reading at any hour of the morning.

My own Circadian Rhythms which I disrupted to write this paper.