Prevention or Treatment- Which would be the Hero to the Battling of

Alzheimer’s Disease?

There is no denial that our human population is getting older. WHO reveals that the average
life expectancy of human in 2013 was 71 years (1), having increased by more than six years since
1990. One of the major health catastrophes resulting from aging population is the emerge of,
referred to Prime Minister David Cameron as “one of the greatest enemies of humanity” (2),
Alzheimer’s Disease (AD). AD, accounting for 60%-80% of dementia, is an irreversible
degenerative neurological disorder causing problems with memory, thinking and behaviors. It
arises from progressive death of brain cells, initiating from the memory center in the hippocampus
to the whole cerebral cortex and cerebellum, leading to cognitive impairment and motion in-
coordination; and finally affecting the brainstem causing immobilization of the normal action of the
heart and lung and eventually lead to death. Identified by the WHO and G8 Dementia Summit as a
“major public health priority”, this incurable disease has affected 44 million people worldwide in
2013, and this is predicted to treble to 136 million by 2050. (4) It is estimated that 5.4 million
Americans have AD. Every 69 seconds, a person in the United States develops AD. By 2050, this
rate will double to a new AD case every 33 seconds. 3 Gender differences are significant in its
incidence, with the cumulative risk for 65-year-old women to develop AD at the age of 95 years
was 0.22 compared with 0.09 for men. (7)

Although the exact etiology of AD largely remains unknown, researchers currently agree
that it is a multifactorial disease, being a result of complex interactions among ageing, genetic,
lifestyle and environmental factors. The primary risk factors for late-onset AD include increasing
age, the presence of APOE ε4 genotype, head injury, family history, low education and low
participation in cognitively stimulating activities. Among them, advanced age is the single most
strongest risk factor as its incidence doubles every 5 years after the age of 65. Nevertheless, up to
5% of the people have early onset Alzheimer's which appears at their 40s and 50s. Besides that,
low physical activity, high fat diet, hypertension, obesity, hypercholesterolemia, diabetes, heart
disease, cerebrovascular disease (CVD), and metabolic syndrome, are the associating factors of
the disease.

So, what has happened in the AD patients' brain? The characteristic findings inside a
diseased autopsy brain are extensive loss of cholinergic neurons in the cerebral cortex and
hippocampus. Because of the abnormal processing of amyloid precursor protein (APP), amyloid
plaques caused by extracellular accumulation of β-amyloid protein are formed. As time goes by,
neurones die through apoptosis and necrosis and phosphorylated tau filaments further aggregate
to form extracellular neurofibrillary tangles (NFT). To date, the exact pathogenesis of the disease
remains unknown and the link between genetic and environmental factors including oxidative
stress, inflammatory and vascular-related pathways is not fully understood. (10)
 It is not easy to confirm the diagnosis of AD while a person is alive. In general, a clinical
diagnosis of AD can be established by doctors through a combination of the following measures:

1. History taking and physical examination;

2. Tests to measure memory, problem solving, attention, counting and language skills. Meta-
analysis study showed that Mini-Mental State Examination (MMSE), Clock Draw test,
Memory Impairment Screen, Verbal Fluency and Informant Questionnaire on Cognitive
Decline in the Elderly (IQCODE) are the several reliable tests to be pursued.
3. Medical tests to rule out other medical diseases including blood tests and urin tests, and
4. PET scan and MRI brain scan.

So far there is no recognized treatment for cure for this disease. To date the most
commonly adopted management of this disease involves three levels of medical interventions:
primary prevention, secondary and tertiary treatment.

Generally management of health issues can be classified as primary, secondary and

tertiary interventions. Primary intervention, or generally regarded as prevention, aims at reducing
the development of a specific disease by eliminating or treating its risk factors. Secondary
prevention aims to detect the disease at an early stage, before any symptom has emerged and
exercise timely treatment to return people to their original health. Tertiary intervention ameliorates
the impact of the ongoing disease and allows patients to maintain an acceptable quality of life.

In the case of AD, patients can remain asymptomatic through the primary preventive
measures. To date, numerous primary preventive methods of AD include cognitive training,
physical exercise, dietary control and screening have been practised. “Cognitive reserve” (CR)
refers to the number of neurons present determining the protection of individuals from cognitive
decline. Study has concluded that CR can be increased through receiving education and engaging
in highly complex mental activities such as memorizing, reasoning and processing. Likewise,
aerobic exercise attenuates progression of loss of synapses and neuropil via facilitation of
neurotrophic factors and neuroplasticity (30).

Evidence also suggests that there is a positive relationship between high blood cholesterol
levels and occurence of AD. Similarly, high blood pressure has been linked to increased risk of
cognitive decline. Therefore, by controlling cholesterol intake and blood pressure by consuming a
low salt and low fat diet, as well as limiting alcohol intake, the chances of developing Alzheimer’s
might be lessen. There are claims that an antioxidant diet, enriching in Vitamin E and C, could
protect the neurons from being damaged by oxygen free radicals produced by highly metabolic
activities in the brain. Systematic reviews have also shown associations between the
Mediterranean diet, which contains high levels of antioxidants of fruits and vegetables, and lower
levels of memory and thinking problems, by reducing the extent of inflammation in the brains of
Alzheimer patients.

Screening methods using brain scans, blood and genetic tests have been shown to be
effective to detect AD a decade before symptoms emerge. Based on the assay of an insulin
receptor, IRS-1, in the blood, researchers could accurately identify potential AD patients a decade
before they develop the symtoms. Brain scan, such as PET Scan, can provide reliable images at
areas affected by beta-amyloid.

To date tertiary treatment of AD mainly involves therapeutic treatment and non-drug

treatments to control the symptoms. Currently approved drugs work by curbing the breakdown of
the chemical acetylcholine (ACEI), a messenger important for memory and learning. The drugs
help to foster communication among nerve cells by keeping acetylcholine levels high. Among this
group of drugs, three of them are commonly prescribed: donepezil (Aricept), galantamine
(Razadyne) and rivastigmine (Exelon). Although ACEIs are generally prescribed to treat patients
with mild to moderate stages of AD, a recent systemic review showed that they produced small
improvements in memory test that may not be clinically meaningful. (ref 6)

A second type of medication which aims to regulate the activity of glutamate, a messenger
chemical involved in learning and memory, is mamantine (Namenda).

Apart from therapeutic drugs, there has been growing research done on gene therapy
involving the introduction of healthy DNA or genes into the diseased cells to halt the development
of AD. An animal study found that, plaque buildup declined dramatically after a few weeks of
replacement of genes to the diseased brain of mice using the mediator of modified cold virus.
There has been a success of transplantation (Cell replacement theory) of neural stem cells or
induced pluripotent stem cells (IPSCs) on mice to halt the accumulation of plaques and tangles.
The theory behind is that neural stem cells can travel to the dentate gyrus part of the hippocampus
and elevate levels of brain-derived neurotrophic factors proteins (BDNFs) within the brain, which
increase synaptic density and improve cognitive ability.

Despite of all these advances of the interventions mentioned above, unfortunately so far
there is no valid evidence to show that AD can be cured. Yet the economic impact of this disease is
costly. It is estimated that the total costs associated with dementia are $604 billion (2010 US
dollars) which is 1% of the world’s gross domestic product.1 In the United States, total direct cots of
AD are US $183 billion in 2011, and are expected to increase to $1.1 trillion by 2050. In light of that
even a very small reduction in the rate of development of AD would have enormous public health
benefits. Very recently, the early results of study using solanezumab, an antibody antagonizing
beta amyloid in the patients' brain showed a successful slow down of memory deterioration in AD
patients. This medication may offer a hope for a potential cure of the disease.

Therefore, there is a growing pressure for researchers and economists to strive for the best
possible solution or strategy to battle this global and evolving disease. They want to answer a
question: Among the three levels of medical measures, which is the most cost-effective one? A
recently introduced approach of “cost-effective analysis” (CEA) to compare the effectiveness of
different medical interventions may be the answer.

Cost-effectiveness analysis is a form of economic analysis commonly used in the field of

health services. It is employed to compare the relative costs and outcomes (effects) of two or more
courses of action. Typically the measurement of CEA is expressed in terms of a ratio where the
denominor is a gain in health from a measure. In medical health sector, “Incremental cost-
effectiveness ratio” (ICER) is the most commonly used measurement to assess and compare the
cost-effectiveness of two medical interventions. It is defined by the difference in cost between two
interventions, divided by the difference in their effect. The ICER can be estimated as:

where and are the cost and effect in the intervention group and where and are
the cost and effect (outcome measure) in the control care group. [1]
Costs are usually described in
monetary units, while effects or outcome can be measured in terms of health status and the most
commonly used outcome measurement is “quality-adjusted life year” (QALY).

QALY is a measurement of the value of health outcomes, including both the quality and the
quantity of life lived. Since health is a function of length and quality of life, the QALY was
developed as an attempt to combine the value of these attributes into a single index number
expressing in terms of “years lived in perfect health”. The basic idea underlying the QALY is simple:
it assumes that a year of life lived in perfect health is worth 1 QALY (1 Year of Life × 1 Utility value
= 1 QALY) and that a year of life lived in a state of less than this perfect health is worth less than 1.
The exact QALY valueis calculated by multiplying a utility value associated with a given state of
health by the years lived in that state: half a year lived in perfect health is equivalent to 0.5 QALYs
(0.5 years × 1 Utility), which is the same as 1 year of life lived in a situation with utility 0.5 (e.g.
bedridden) (1 year × 0.5 Utility). QALYs can then be incorporated with medical costs to arrive at a
final common denominator of ICER.
 ICER is commonly used by the health organizations to calculate the cost effectiveness of
each individual intervention and employed as a guildeline to justify the allocation of healthcare
resources for different interventions. As an example, the National Institute for Health and Care
Excellence of United Kingdom adopts a nominal cost-per-QALY threshold of £20,000 to £30,000 as
a guildeline of cost-effectiveness for different medical measures. [2] Should ICER of a given
intervention above this threshold it will be deemed too expensive and thus should not be funded,
whereas if the ICER lies below the threshold the intervention can be judged cost-effective.

A recent cost-effective study using an algorithm deriving QALY in terms of MMSE score and
state of independent and institutional living, concluded that “early intervention is clearly indicated
for current symptomatic treatments, which are likely to be most cost-effective when applied as
early as it is possible to diagnose AD” and “intervention” was most economically beneficial when
applied around 2 years prior to the time of standard diagnosis and suggested that cost-effective
early detection and intervention should be an achievable goal in earlier stages of disease. A range
of different intervention effects and costs associated with early diagnosis might be manageable or
even more beneficial in terms of overall healthcare costs.” (ref)

Another study comparing the total costs of early diagnostic and intervention costs with the
total costs of late intervention concluded that an earlier identification of AD would yield overall
savings to the state of approximately US$10,000 per diagnosed patient. (Ref1)

How effective is medical treatment initiated early in AD? An analysis predicting the impacts
of early intervention with AD treatment based on different parameters of age, sex, marital status
and initial MMSE score, concluded that early drug treatment appears to slow the decline by about
1 to 2 MMSE scores per year. (ref3)

Nevertheless, does this mean that universal screening of the potential patients should be
introduced globally? The answer is not straight forward. There are numerous arguments against
screening for early diagnosis and treatment. There is a great concern that many people will
experience fear and anxiety about being labeled with the disease. Furthermore, up to now, the
benefits of the current medical therapies are marginal, the saving from pharmacological treatment
may not be obvious. (ref4)

After systemic analysis of all the evidence, I would like to make my conclusion on this
argument:
There are more evidence to suggest that prevention or initiation of early treatment after
early diagnosis is more cost-effective than late drug treatment. Apart from the economic
consideration, early diagnosis may also be beneficial in the following aspects:
 1. Patient may have more time to plan for the future;
2. Patient may have less concerns about the future;
3. Patient may have more time and be prepared to organize supportive service, making it
easier for the patients and their family to manage the disease, make decision about care,
transportation, financial and legal matters.
Therefore early detection and intervention should be an achievable goal in an early stage of
AD.
However, further resources and attention have to be placed globally for us to have a better
understanding of this disease so that it can be eradicated from the globe as we did to the small-pox
nearly a century before.

“Early identification and treatment of Alzheimer's disease:

ref 1.
Social and fiscal outcomes”
ref3. Bullock R, Dengiz A. Cognitive performance in patients with Alzheimer's
disease receiving
cholinesterase inhibitors for up to five years. Int J Clin Pract 2005;59:817–22.
[PubMed: 15963209])
ref 4 “Early identification and treatment of Alzheimer's disease:
Social and fiscal outcomes”

Generic Brand Approved Side Effects

For
donepezil Aricept All stages Nausea, vomiting, loss of appetite and increased frequency
of bowel movements.
galantamine RazadyneMild to Nausea, vomiting, loss of appetite and increased frequency
moderate of bowel movements.
memantine Namenda Moderate Headache, constipation, confusion and dizziness.
to severe
rivastigmine Exelon Mild to Nausea, vomiting, loss of appetite and increased frequency
moderate of bowel movements.
vitamin E Not Not Can interact with antioxidants and medications prescribed to
applicable approved lower cholesterol or prevent blood clots; may slightly
increase risk of death.

Table 1. Drug Treatment of Alzheimer's disease