The document discusses Alzheimer's disease (AD), including its prevalence, risk factors, effects on women, guidelines for prevention, and management and treatment options. Some key points: - AD is the 6th leading cause of death in the US and is projected to nearly triple by 2050 without medical breakthroughs. - Risk factors include genetic factors like the ApoE4 gene as well as environmental/lifestyle factors such as diet, education level, and exposure to toxins. - Women are disproportionately affected, holding nearly two-thirds of the 5.1 million current cases. Estrogen levels and ovarian decline may contribute to this. - Prevention guidelines focus on education, awareness, and lifestyle modifications. A

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Erica Hefner
Introduction
Americans living with Alzheimer's disease (AD) is growing to cost an estimated $250 billion per
year. AD us claiming 5.4 million Americans in 2016.1
One in nine people ages 65 and older has AD. By
mid-century, AD will progress to claim someone in the United States every 33 seconds.1
Without the
development of medical breakthroughs to prevent or cure the disease by 2050, the number of people
with AD may nearly triple, to a projected 13.8 million, with a price of 300 billion per year.1
AD is
officially listed as the sixth-leading cause of death for people over 65 in the United States.1
As the
population of the United States ages, AD is becoming a more common cause of mortality. In 2013, over
84,000 Americans died from AD according to official death certificates; however, in 2016, an estimated
700,000 people with AD will die, and the disease likely will contribute to many of those deaths.1
Etiology
Several genetic mutations increase amyloid-beta (AB) production and are early-onset, familial
forms of AD. AB is the primary constituent of extracellular plaques, typically considered one of the two
pathological hallmarks of AD, whether inherited or sporadic. The extent to which plaques and tangles,
are responsible for neuron degeneration or merely markers of other fundamental processes gone awry
continues in a debate, particularly the more common, late-onset form of the disease. AB is generated by
the cutting of a larger amyloid precursor protein by two enzymes, (beta and gamma secretase), a process
occurring in all cells in the body.2
Once cut, fragments of AB that lie outside the cell may aggregate
into small, toxic oligomers which can further concentrate into fiber-like structures. Down syndrome,
caused by an extra chromosome (number 21), carries an increased risk for early-onset AD.3
Postmortem
cranial examinations show amyloid plaques, tau tangles, excessive oxidative stress, and lipid
peroxidation beginning at age 8.4,5,6
The amyloid precursor protein gene is located on chromosome 21
and its over-expression leads to excessive production of such protein. A nearby gene is responsible for

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producing a protein that influences cholesterol transport within the cell and appears to increase the
likelihood that AB plaques will form from the excessive levels of amyloid precursor protein.7
A third
nearby gene is responsible for producing the enzyme superoxide dismutase (SOD1). Overexpression of
SOD1 contributes to an enzyme imbalance that results in excessive free-radical production, oxidative
stress, and damage to critical cellular components.5
The more common, late-onset, sporadic form of AD has no known genetic causes. However, the
ApoE4 gene, increases the risks of developing AD.8,9,10
One copy of the ApoE4 gene is present in 15
percent of the US population.19 Caucasians found to have a higher risk, of carrying one copy and nearly
15-fold in those carrying two copies of the ApoE4 gene.8
The risks among African Americans varied,
averaging a 1.1 and 5.7-fold increase for African Americans taking one and two copies of the gene.
Any Issues Unique to Women
Women, in general, have a better verbal memory than men, a difference that emerges after
puberty and continues, in healthy individuals, for life. Women at risk for AD will experience steep
memory declines just after menopause. A woman’s overall lifetime risk of developing AD is almost
twice that of a man, and not only because women live longer. APOE variants consist of APOE2,
APOE3 andAPOE4. Commonly, people carry two copies of the APOE3 gene variant.11
One in five
females carry APOE4.12
Healthy women who inherit APOE4 variant are twice as likely to develop
mild cognitive impairment or AD, compared to males of similar demographics, women have a higher
overall risk for the illness. Depression and CVD, are themselves risk factors for AD. Two-thirds of the
5.1 million people currently suffering from AD are women.13,14
Women, statistically are charged with
caring for ones with the disease, meaning they shoulder both the risks and the burdens.
Recent studies have connected estradiol, the primary form of estrogen that affects the brain, to
known risk factors for AD.15,16,17,18
Current research is focusing on sex differences early in the aging
process, as women transition through menopause.19
Evidence suggests ovarian decline plays a key role

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in the changes in the brain as women age. Different sections of the brain atrophy at various rates
depending on sex,20
a finding that may relate to more severe AD pathology found in women than men in
postmortem brain studies.
Risk Factors
The ApoE4 gene provides an example of complex gene-environment and gene-gene-
environment interactions. ApoE4 increases risks for AD, and Western lifestyle factors are emerging as
key to these risks. Illustrated in a 21-year Swedish observational study, ApoE4 alone increased the risk
for AD by a factor of 2.83. When compounded with lifestyle factors, the ApoE4-environment
interactions increased the risk by a factor of 11.21
Environmental factors increasing risk included alcohol
drinking, smoking, and Western-type diet (specifically reduced intake of polyunsaturated fat and
increased intake of saturated fat). Lifestyle interventions may substantially modify dementia risk,
particularly among genetically susceptible individuals.22
Epidemiologic studies also support the view that Western lifestyle, including diet, is a key driver
of ApoE4-associated hazards. Several studies of AD in Nigerian-Yoruba elders who consume a low-fat,
low calorie, and predominantly plant-based diet23
found no significant association between ApoE4 and
AD. They also showed much lower age-adjusted rates of AD. These findings contrasted sharply with the
African-American control population in this study, which showed higher age-adjusted incidence of AD
and a significant association of ApoE4 with the disease.24
Inflammatory cytokines activate microglia, a potent agent of neurodegeneration.25
Elevated
cytokines increase the expression of COX2 in the endothelium, which produces PGE2. PGE2 can
stimulate amyloid-beta production, another possible mechanism that may connect inflammatory
particulate and air pollution with AD.25
Since PGE2 is derived from omega-6 fatty acids, the relatively
high omega-6 fatty acid content of the Western diet (along with the low omega-3 content) may intensify
PGE2 production, increasing amyloid-beta formation and the risk of AD. 25

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Interestingly, one study examining the role of ApoE4 in chronic occupational lead exposure
found that ApoE4 increased the adverse effect of lead on neurobehavioral function, including memory.26
Studies implicating lead, pesticides, PCBs, particulate air pollution, and aluminum have recently
published. In one recent study, 21 percent of more than a thousand patients presenting to a university
clinic for cognitive disorders had histories suggestive of toxic environmental and occupational
exposures. A history of toxic exposure significantly lowered the age of onset of cognitive decline, an
effect equivalent in magnitude to that caused by carrying two copies of the ApoE4 gene.26
Aluminum may contribute to neurodegenerative disease as seen in the relationship between
dietary aluminum and memory loss. The documented exposure level at which memory loss begins to
increase (0.49 mg aluminum/kg/day) was well within the range of human dietary exposure. Half of all
Americans ingests the upward range of 1.36 mg/kg/day, as additives in commercially processed foods
and beverages with pancake/waffle mixes and frozen products, and ready-to-eat pancakes containing the
most aluminum. Consuming the high-aluminum varieties of these foods on a regular basis could lead to
accumulation in hippocampal neurons 27
, plaque and tangle formation 28
, and induced gene expression
promoting inflammation and cell death.
Evidence has begun to link air pollution with neurodegenerative disease. Such proof includes
human and animal studies that combine histopathology, neuroimaging, cognitive testing, and limited
epidemiology. Recent postmortem studies comparing brain tissue from lifelong residents of cities with
severe air pollution with brain tissue from lifelong residents of low-air-pollution cities showed evidence
of inflammation and AD-type brain tissue pathology in the inhabitants of air polluted cities, compared to
the residents of relatively clean air cities.
Guidelines for Prevention

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The CDC published the Healthy Brain Initiative, a framework for public health agencies wanting
to plan programs in promoting cognitive functioning, addressing cognitive impairment and AD, and
helping meet the needs of caregivers.29
They have specific action items listed under four main areas:
workforce, educate, monitor, partner. Under Educate and Empower the Nation, generic
recommendations include statements: Identify and promote culturally-appropriate strategies designed to
increase public awareness about dementia, including AD, to reduce conflicting messages, decrease
stigma, and improve early diagnosis. Improve consistency of cognitive health messages among national,
state, and local levels using models such the National Diabetes Education Program.29
The inclusion of AD in Healthy People 2020 underscores the growing recognition of AD as a
public health crisis.30
It also reinforces the need for state and local public health officials to address this
crisis now. Under the topic, Dementia ADHP2020 set goals to decrease morbidity and costs associated
with and enhance the quality of life. They plan to accomplish the following two objectives: 1.) Increase
those diagnosed and caregivers with awareness of the diagnosis. 2.) Reduce the percentage of
preventable hospitalizations in persons with diagnosed AD.30
Although the mechanisms of antioxidants, vitamins, fat, and carbohydrates on AD are not
precise, reducing oxidative stress and amyloid beta-peptide accumulation is considered to play a role in
the process of AD. In addition to antioxidant characteristics, polyphenols demonstrate a variety of
neuroprotective properties in animal and in vitro studies. The polyphenol curcumin, in turmeric, has
been shown to inhibit amyloid-beta aggregation and fibril formation in vitro. When fed to aged AD-
prone mice with advanced amyloid accumulation, curcumin reduced levels of amyloid and plaque
burden.31
Similarly, blueberry extracts, highly concentrated with polyphenols, have been shown to
prevent and even reverse age-related deficits in neuronal signaling and cognition in rats. Blueberry
supplementation was also shown to increase neurogenesis and improve memory performance in aged

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rats.32
Polyphenols also act as free radical scavengers, regulate nitric oxide, inhibit cell proliferation, and
reduce the immobilization of leukocytes.33
The Nurses’ Health study, which followed up 16,010 older
participants for an average 6.4 years, published on the association between antioxidants and cognition.
About flavonoids (berries in particular), a higher intake of strawberries and blueberries will result in
slower cognitive decline at following up.34
Management and Treatment
When the brain does not clear proteins correctly, neurological problems arise. Introducing a
plasmid that can be transcribed and translated into an antibody targeting these proteins may help the
progression of AD. In theory, the antibodies can be used to rid the proteins in the CNS.35
Cannabinoids
help prevent beta-amyloid plaques by decreasing microglial activation. Cannabinoid receptors (CB1)
throughout the nervous system and activation of these receptors reduce microglial activity; specifically
reduces astrocyte reuptake of glutamate (an excitatory neurotransmitter).36
Research is leading us to the Mediterranean diet in reducing cognitive decline and AD. One
study following over 2,000 New York residents found that adherence to the Mediterranean diet over four
years was associated with a risk of AD that was reduced by more than a third had a markedly lower
mortality risk as well as nearly four years longer survival. Inspired by the Mediterranean, the MIND diet
is has therapeutic benefits for cognitive function.37
The MIND diet has 15 dietary components, including
10 “brain-healthy food groups” green leafy vegetables, other vegetables, nuts, berries, beans, whole
grains, fish, poultry, olive oil and wine and five unhealthy groups that comprise red meats, butter and
stick margarine, cheese, pastries and sweets, and fried or fast food.37
The MIND diet includes at least
three servings of whole grains, a salad, and one other vegetable every day along with a glass of wine
(those carrying the ApoE4 gene should avoid wine). It also involves snacking most days on nuts and
eating beans every other day or so, poultry and berries at least twice a week and fish at least once a

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week. Dieters must limit eating the designated unhealthy foods, especially butter, cheese, and fried or
fast food.37
Simultaneous supplementation with multiple micronutrients (fatty acids, phospholipids, vitamins
E, C, B6 and B12, and folic acid) might be required synergistically to increase brain levels of molecules
that are essential building blocks of brain synapses.38
Souvenaid is a nutritional drink approach
providing essential nutrients to help support memory in aging adults. Souvenaid contains a patented
combination of nutrients which includes omega-3 fatty acids, choline, uridine monophosphate and a
mixture of antioxidants and B vitamins.38
Melatonin has been shown to be neuroprotective in some animals and in vitro studies. Melatonin
effects include inhibition of beta-amyloid neurotoxicity, oxidative stress in transgenic mouse models of
AD, and proinflammatory cytokine production induced by amyloid-beta in rat brains. Studies in humans
show that although melatonin levels normally decline with age, the levels are more sharply reduced in
people with AD, even in the earliest stages.39
Myths and Misconceptions
Micronutrient and macronutrient deficiencies are common in AD, and it is clear that
undernutrition has significant consequences for health, quality of life and survival. Loss of body weight
seems, on the one hand, to be a natural part of the condition, with complex multifactorial determinants,
and yet to be amenable to intervention.40
It is important not to assume that a person who does not eat,
does not want to eat. They may not recognize food (agnosia) or not be able to feed themselves
independently (apraxia). Caregivers should be educated to look for non-verbal clues such as body
language and eye contact as a means of communication.40
Difficulties in swallowing (oropharyngeal
dysphagia) can lead to a risk of aspiration. It is important that the person with dementia be alert,
comfortable, and sitting up in a good position before feeding is attempted. The advice of an appropriate

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specialist (speech and language therapist, occupational or physiotherapist) may be needed. It may be that
while necessary information should be provided to all families, more real services should be focused on
those developing feeding difficulties or undernutrition.40
Conclusions
With an estimated 7.7 million new cases each year1
, dementia prevention is an urgent priority,
both to reduce the incidence and slow the progression of the condition. We need to identify important
risk factors, particularly those that can be modified. Nutrition, brain development, and adult brain health
are linked together by complex pathways across the life course, suggesting multiple opportunities for
prevention.
Key Resources
Research Challenges and Opportunities (ADRD) Summit, bringing together an international group of
experts and members of the public to develop research priorities for accelerating the development of
therapies for FTD, Lewy body, mixed and vascular dementias. NINDS convened the second ADRD
Summit on March 29-30, 2016 to assess progress and revise and update the ADRD recommendations,
which will be posted on the NAPA website later this year.
http://www.ninds.nih.gov/news_and_events/index.htm
NIA operates the AD Education and Referral Center (ADEAR), the primary Federal Government
resource for information on AD research and care. The Center educates the public about the latest
research findings and provides evidence-based information about AD and other dementias, participation
in clinical trials, and caregiving, is available for people with the disease, their families and caregivers,
health care and social service providers, and the public.
https://www.nia.nih.gov/alzheimers
At, http://www.alz.org/ there is a massive amount of information on all different aspects of the disease
and response to aging. To bring light to a specific PowerPoint, Psychological Outcomes when exposed
to green spaces contains a Program Logic Model for a framework to plan gardening programs among
residential care facilities. It is an excellent approach to interdisciplinary adult programming with
therapeutic horticulture.
http://www.alz.org/documents/tex/dementia_and_the_environment.pdf
Nutrition Guide For Alzheimer’s:
http://www.nchpad.org/463/2341/Nutrition~for~Alzheimer~s~Disease

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