Download By Majid Fotuhi, MD, PhD

By Majid Fotuhi, MD, PhD
ear of developing Alzheimer’s disease (AD), far more
than the disease itself, has become an epidemic and a
major source of concern for Baby Boomers in the US.
Elderly beyond the age of 80 are the fastest growing segment of the population, and many of them who experience cognitive decline receive the diagnosis of AD. Their children, mostly Baby Boomers, now wonder if they are next.
Common questions that they have may include:
1. My mother in her 80s has been just diagnosed with AD.
When do you think I will get it?
2. What can I do to reduce my risk of developing AD? Is it
possible?
3. I can never remember anyone’s name and sometimes feel
embarrassed for not remembering even the names of people I
have known for a long time. I have AD, right?
4. Ginkgo biloba, vitamin E, curcumin, and fish oil all seem
to be good for warding off AD. Which one do you recommend?
The concern for developing this dreadful disease is not limited to the lay population. Recently, a physician with a busy practice called me to request an earlier appointment. During our
phone conversation, I learned that he is 50 years old and has been
forgetting names and appointments. His family believes that he
has developed AD. Meanwhile, he works full-time, publishes articles, and engages in many social and professional meetings and
gatherings. I could hear from his trembling voice that he was truly
concerned that he would soon develop AD.
Among the more than 78 million Baby Boomers in the US,
far fewer than one percent have been diagnosed with AD. Thus,
more than 99 percent of this population does not have AD and
F
34
logically should not worry about it. However, they do worry.
Their concerns are real and must be addressed. A successful strategy to provide reassurance and to help Baby Boomers take steps
to improve their brain health is easy. It requires educating them
regarding causes of short-term memory problems in their current
day-to-day life and making them appreciate their risk factors for
developing dementia in their last decades of life.
Common Cause of Poor Short-Term Memory
Forgetting names and occasional appointments more likely
occurs in Baby Boomers with multiple medical issues (e.g., obesity, heart failure, or chronic uncontrolled pain), depression, medication side effects, stressful lifestyle, long work hours, constant
fatigue, and most commonly, lack of adequate sleep.1 Some of the
common causes of poor sleep quality include insomnia, restless
legs syndrome, frequent urination, obstructive sleep apnea
(OSA), and anxiety. Many patients with OSA do not realize that
their grogginess, lack of energy, and difficulty with concentration
during the day stem from frequent hypoxia and awakenings that
they experience during the night. Heart patients who have low
cardiac ejection fraction also suffer from low levels of oxygen to
their brains, and as a result, their cognitive abilities decline.
Patients with untreated depression have difficulty paying attention and often report being extremely forgetful. Treating and optimizing medical issues produces a noticeable improvement in
memory functions for our patients and improves their confidence
that they do not have early signs of AD.
Information overload may be yet another factor that hinders
memory. Thanks to a surfeit of technological advances, from
Practical Neurology
March/April 2009
pagers, BlackBerries and text messaging to e-mails, websites, and
podcasts, Baby Boomers are bombarded with loads of information in a constant stream. Somehow, their expectation is that they
should remember details from these many different forms of communication and be able to keep up with them. Never in the history of our civilization have people been exposed to this degree of
information on a daily basis. Our middle-aged busy patients need
to adjust expectations in this regard. I sometimes suggest they
limit checking e-mails (or playing with their BlackBerries or
iPods) to once every three hours to reduce their flow of incoming
data. They also would benefit from a five- to ten-minute relaxation break (e.g., meditation) during their hectic days.
When Baby Boomer patients relate stories of forgetting names,
I remind them that learning and remembering people’s names can
be considered a skill, similar to dancing or learning a new language. Paying attention, persistence in memorizing a name at the
first encounter, and repetition of a new name throughout the conversation are simple means of committing a name to memory.
onset AD and late-onset AD.
With early-onset presenile
Alzheimer dementia (quite rare,
affecting less than one percent of the Baby
Boomer population), patients lose their cognitive abilities at a
rapid rate.2 They cannot function at their jobs and, within one or
two years, have difficulty maintaining their finances or even
some of their routine activities of daily living. This form of
dementia has a strong genetic component, and indeed, patients
who have family members with early-onset AD are at significantly increased risk. In contrast, late-onset dementia (beyond age
65) has a lower genetic component.3 A person in his 70s has
approximately a two percent risk of developing dementia. His
risk may be doubled (to four percent) if he has parents who experienced dementia in their 80s. In other words, a patient has
about a 96 percent chance of remaining cognitively healthy—if
he has no other risk factors.
Risk Factors for Cognitive Decline with Aging
Heredity and AD
Addressing medical, psychological, and lifestyle issues are the
first steps toward helping Baby Boomers identify ways in which
they can improve attention and memory. An equally important
step is educating them regarding the difference between early-
March/April 2009
A number of risk factors associated with lifestyle choices and cerebrovascular issues increase up to 16-fold the risk of developing
cognitive impairment with aging.4,5 Thus, a Baby Boomer with
obesity, diabetes, hypertension, smoking, sedentary lifestyle, high
cholesterol, strokes, and chronic stress is far more likely to devel-
Practical Neurology
35
AD Prevention
op dementia than her neighbor who is otherwise well but has
parents with AD.
Chronic untreated hypertension can literally lead to smaller
brains.6,7 Similarly, chronic OSA can cause 18 percent cortical
atrophy in frontal lobes and even in the hippocampus, the brain
region most essential for short-term memory.8,9 Uncontrolled
diabetes is yet another condition associated with thinning of the
cortex with age.10 These factors are extremely important, and
Baby Boomers worried about AD can start their efforts toward
improving brain health through addressing their risk factors.5,11
To help patients identify and recognize their risk and protective factors, I have developed a screening questionnaire (Table 1).
Their particular score on this test provides an opportunity for me
to talk to them about setting priorities on ways in which they can
lower their chance of developing dementia in their 80s. Simple
lifestyle changes during midlife have the potential to serve as
“primary prevention” strategies for late-life dementia (Fig. 1).
New Way of Thinking About Aging & Dementia
In 1997, Snowdon, et al.’s pivotal study changed the way neuroscientists view the brain with aging and dementia.12 The Nun
Study showed that many elderly women had large loads of AD
tangles but no hint of cognitive impairment. The inconsistency
between severity of Alzheimer neuropathology and degrees of
dementia could be explained by the coexisting number and severity of strokes in the brain. The combination of Alzheimer pathology and vascular pathology—not either one of them alone—
turned out to be the deciding factor for development of cognitive
impairment in the majority of their elderly participants (Fig. 2).
Findings from other research groups confirmed the results of
the Nun study. For example, it was shown that presence of subcortical lacunar strokes can increase the risk of dementia five- to
six-fold.13 Extent of plaques and tangles may be similar in elderly with dementia and those with no evidence of dementia, again
supporting the notion that Alzheimer pathology by itself may
not be sufficient for triggering symptoms of cognitive deterioration among elderly.14,15 The net conclusion of the recent literature
in this field suggests that a substantial number of elderly can harbor high amounts of plaques and tangles in their brains and have
no signs of dementia—if their brains are otherwise healthy. In
fact, it is becoming increasingly difficult to justify diagnosing
those 80 and older with AD, as plaques and tangles seem to be
only part of a combination of culprits in late-life dementia.16
Neuroprotective Factors
Exercise. Brain plasticity continues throughout life and is not
limited to childhood. In a study by Kramer et al., retired elderly
were invited to participate in a “walking” study.17,18 One group
was randomly assigned to walk three times per week for six
months. Another group performed stretching exercises, and a
36
third group continued with their routine lifestyle, which did not
include significant physical activity. At the end of six months,
MRIs of the brain were obtained and were compared to MRIs
obtained at baseline. A three percent increase in cortical areas in
frontal lobes was noted in the group that walked three times per
week. Brain volume growth was accompanied by a 15 percent
improvement in performance in cognitive tests. In short, a simple walking regimen resulted in actual expansion of cortical
areas, comparable to being three years younger, after only six
months of regular exercise. More recent evidence suggests that
even hippocampus shows plasticity with physical exercise.17,18
One potential mediator for this increase in brain size appears to
be brain-derived neurotrophic factor (BDNF).19,20 Blocking
BDNF in comparable animal studies reduced the amount of
brain plasticity with exercise.
Brain stimulation. Intensive brain stimulation can expand
the size of the cortex as well. May et al. in Germany obtained
brain MRIs in a group of medical students before and after three
months of intense studying in preparation for their national
board exams.21 MRIs revealed a significant increase in brain volume in parietal lobes and hippocampus. Parietal lobe expansion
remained significant but plateaued three months after students
had completed their exams, when they were no longer working
hard in memorizing long lists of medical terms. In contrast, hippocampal expansion continued during these three resting
months. The surprising growth in hippocampus may be in part
due to its unique ability for neurogenesis throughout adult life.
These results clearly indicate that cognitive stimulation can modify the volume of cortex and hippocampus at both microscopic
and macroscopic levels.
Diet. Along with studies highlighting the importance of exercise and brain stimulation, numerous others have highlighted the
critical role of diet in brain health.22,23 Inflammation is a key part
of neurodegeneration with aging. Levels of inflammatory markers (such as C-reactive protein) tend to be higher in individuals
with dementia compared to those without cognitive impairment.24 Nonsteroidal anti-inflammatory drugs (NSAIDs), especially ibuprofen, have been associated with some reduced risk of
developing AD.25 Though these findings remain controversial,
they support the important role of inflammation in brain aging.
Findings from The Cache County Study revealed a significant
reduction in risk of AD in individuals who consume high quantities of fruits and vegetables or those who take vitamin E or vitamin C supplements.26,27 We recently reported that the combination of NSAIDs and antioxidant vitamins (E and C) can lead to
“better” cognitive performance in elderly.28 The elderly at high
risk for developing AD gained a synergistic benefit from taking
antioxidant vitamins and anti-inflammatory agents together. The
Cache county results were based on data from approximately
5,000 participants who were monitored for eight years.
Practical Neurology
March/April 2009
Table 1. Baby Boomer Memory Quiz. A full-size PDF of this survey is avilable for download at
practicalneurology.net. Look for this article under “Current Issue,” and see the last page.
Our recent systematic literature
review supports a strong neuroprotective
role for omega-3 fatty acids in preventing
cognitive impairment with aging.29 Those
who consume two or three fish meals
every week and/or take fish oil supplements consistently perform better than
those who do not. These observations
require further confirmation by longterm clinical trials; numerous studies
have been in agreement that reducing
inflammation in the brain through diet
(rich in fruits, vegetables, and omega-3
fatty acids) may be a key step toward better brain health.30
Ten Steps Toward a
Healthier Brain
Late-life brain health depends to a large
degree on lifestyle choices during
midlife.1,31 Recognizing and addressing
risk factors and neuroprotective strategies that impact brain volume have now
gained more importance and provide
support for recommending lifestyle
changes that can potentially provide primary prevention for late-life dementia
(Fig. 1). These recommendations can
only be based on observational studies in
large cohorts of participants monitored
for several years or decades. Clinical trials
to confirm how mid-life lifestyle changes
may reduce risk of late-life dementia are
unlikely to be conducted, due to challenges in monitoring large numbers of
participants over decades and having
adequate control (placebo) groups.
In The Memory Cure: How to Protect
Your Brain against Memory Loss and
Alzheimer, I highlight (based on my review of more than 2,000
papers in the field) 10 steps I recommend to my Baby Boomer
“worried well” patients.1
1. Take control of your blood pressure. High blood pressure
is the silent killer for the brain. Individuals who have higher blood
pressure throughout midlife are two or three times more likely to
develop cognitive impairment in their 80s.5 Some studies suggest
that chronic hypertension actually causes brain atrophy.6,7
Controlling high blood pressure can reduce the risk of developing
dementia significantly.32 A recent study showed that people taking
antihypertensive medications had a lower load of amyloid plaques
March/April 2009
than those who did not have hypertension, suggesting that these
medications may alter the neuropathology in AD.33
One out of four Americans has high blood pressure; more than
three-quarters of these patients do not treat their hypertension successfully. Given the increased risk of coronary artery disease, maintaining a healthy blood pressure should be a top priority for all of
our patients, regardless of whether they are concerned about their
heart health or their brain longevity. Simple steps to lower blood
pressure without medications include reducing the amount of salt
in the diet, walking daily, and reducing stress as much as possible.
However, for those with serious hypertension (systolic blood pres-
Practical Neurology
37
AD Prevention
Figure 1. Several observational studies have provided support for
the concept that lifestyle changes during midlife can serve as
strategies for the primary prevention of dementia.
Fig.1&2: Fotuhi M. The Memory Cure: How to Protect your Brain against
Memory Loss and Alzheimer's Disease. New York: McGraw Hill, 2003,
with permission.
sure >160), medications are often necessary. Our middle-aged
patients interested in keeping their brains young must take their
hypertension (mild or severe) seriously.
2. Lower your cholesterol. Hypercholesterolemia accelerates
risk of coronary artery disease and cerebrovascular disease.34,35
Cholesterol-lowering medications, perhaps in ways beyond lowering cholesterol, have been shown to reduce the risk of strokes.
As strokes, small or large, are strong players in determining brain
health, lowering cholesterol should be a priority for healthier
brain.36 For those with only mild hypercholesterolemia, a change
in diet may be sufficient. A special attempt should be made to
increase HDL, as low HDL may be as detrimental as high LDL.
Statins have been associated, with mixed and unconvincing
results, with lower risk of AD. Clearly, if a patient has high cholesterol, he or she needs treatment. The current literature does
not support prescribing statins to otherwise healthy individuals
with normal cholesterol for the sole purpose of warding off AD.35
3. Homocysteine, vitamin B12, and folate. Absorption of
vitamin B12 from gastrointestinal mucosa diminishes with age.
Incidence of low B12 and high homocysteine increases with each
decade of life.37,38 Those with significant B12 deficiency have significant cortical atrophy and cognitive impairment.39 B12 supplements improve concentration and attention; patients often
report “increased energy” when their B12 levels are replenished.
Folate supplementation diminishes risk of dementia.40,41
Surprisingly, several studies have shown that B12 treatment does
not necessarily produce the same effect.42 Low levels of B12 may
be associated with other biochemical abnormalities (e.g., low
folate or B6) that contribute to developing dementia. While
researchers continue to explore the details of the link between
low B12 and risk of dementia, it is prudent for our patients to
have normal B12 levels. I often recommend maintaining B12
levels within 500–1000 pg/lit.
4. Eat a diet rich in antioxidants and fish. In addition to
38
high levels of vitamins
E and C, fruits and
vegetables contain
essential vitamins and
Suppminerals.43
lementing rat diet
with blueberries has
been shown to
increase
cognitive
function and “exploring behavior.” Aged
animals that receive
additional blueberries
perform similar to
young counterparts.44
Fish consumption has
also been shown to improve cognitive performance and, in some
studies, shows benefit in reducing the risk of dementia.29 Thus, we
can recommend to all my patients (without any hesitation) eating
a heart-healthy diet that contains four to five pieces of fruits and
vegetables per day and two to three servings of fish every week.
Due to financial and practical issues, no clinical trial can ever be
performed (in a double-blinded placebo control fashion) to establish the association between diet during midlife and risk of latelife dementia. However, available data from observational studies
remain fairly convincing, especially for the Mediterranean diet.
For Baby Boomers interested in taking supplements instead
of eating fruits, vegetables, or fish, I recommend vitamin E, vitamin C, curcumin, and long-chain omega-3 fatty acids such as
DHA and EPA. Curcumin, a natural NSAID with no significant
side effects, can reduce amyloid accumulation and aggregation.45,46 Plans are now underway to start a clinical trial for this
combination (MemoGuard) to establish its exact effectiveness in
enhancing cognitive function and reducing risk of dementia in
patients with mild cognitive impairment. Gingko biloba has
been studied extensively during the past 10 years; double-blinded clinical trials have failed to show any convincing results for
recommending it for either prevention or treatment of dementia.47,48 In general, some supplements may have a potential role
for improving brain health. However, they are not “magic bullets” for preventing dementia. They may help cognitive function,
but only in the setting of other heart-healthy lifestyle choices.
Drinking one glass of wine with dinner might have modest
neuroprotective effects, as well.49 However, the strength for such
recommendation is minimal compared to other factors, such as
controlling blood pressure. Excessive alcohol consumption itself
can cause brain atrophy.
5. Protect your brain. Head trauma has been associated with
cognitive impairment late in life.50,51 Shrinkage of hippocampus
has been documented in veterans with severe head trauma and
Figure 2. Multiple small subcortical strokes or large cortical
strokes contribute to a higher
risk of “vascular” dementia
(upper pictures). Plaques and
tangles in the hippocampus
and cortex increase the risk of
Alzheimer-type dementia
(lower picture). Either of these
factors, strokes or AD, by
themselves may not trigger
significant cognitive impairment in elderly (silent dementia). However, their combination causes manifestation of
dementia symptoms more
readily—and at an earlier age.
Practical Neurology
March/April 2009
coma in the battlefield.52 Traumatic brain injury (e.g., in boxers)
increases the amyloid load in the brain, thus suggesting a potential mechanism for late-life dementia.53,54 Trauma to the brain may
also tear white matter bundles between the cortical and subcortical areas.55 It may even affect the hemodynamics of blood flow in
the brain. Most patients are aware of the negative impact of head
trauma, but a reiteration about the importance of wearing seatbelts and helmets is prudent.
6. Sharpen your senses. Lack of sleep, medication side effects,
and difficulties with vision or hearing can impair the acquisition of
new information. If information is not firmly registered in the
brain, it cannot be retrieved later. I often highlight the importance
of adequate sleep and maintaining “fresh senses,” for better memory acquisition both in the short term and in the long term.
OSA, quite common in the US, has a direct link to short-term
memory loss as well as dementia.56,57 Patients often feel tired and
groggy in the morning and complain of not being able to pay
attention. Given the critical importance of sleep apnea in causing
memory loss, I always carefully obtain history regarding sleep
issues, snoring, and “dozing off” in meetings or at traffic lights.
Interestingly, most patients do not realize that their daytime hypersomnolence may indeed be related to their snoring at night and to
their obesity. Educating patients about this connection often helps
awaken them to the importance of hypoxia associated with their
sleeping pattern. OSA is also associated with hypercoagulability,
hypertension, and increased risk of myocardial infarction.58 In
addition to improving memory and lowering risk of brain atrophy
with age, treating sleep apnea can be lifesaving.
Some Baby Boomers may sleep only four hours per night,
lead busy social and personal lives, and manage multiple large
projects simultaneously. They may receive phone calls, e-mails,
and pages 12 to 14 hours per day. If they are concerned about
forgetting names and appointments, they need to consider
reducing working hours and pay more attention to their sleep.
7. Exercise. Physical activity is the best medicine for preventing memory loss, both in the short- and long-term.17,18 Improved
blood flow to the brain with exercise is associated with generation
of new blood vessels. The brain is a vascular organ that receives 20
percent of the blood from the heart (considering that it accounts
for two percent of body weight, it receives 10 times its share of
cardiac output). Better vascular health for the brain is important
for thinking clearly, making better decisions, and remembering
more. Exercise also improves HDL-to-LDL ratio, reduces stress,
lowers risk of heart attacks, and enhances mood.
Baby Boomers often complain of “lack of time” for regular
exercise. If they indeed are serious about improving their memory and cognitive health, they need to be serious about engaging in
regular physical activity. They can start with as little as 15 minutes
of walking per day and gradually increase it to 45 minutes per day.
8. Jog your brain. Increased brain stimulation is linked to
March/April 2009
lower risk of AD.59 “Use it or lose it” applies to the brain as much
as to muscles. Neurons can grow new synapses with brain stimulation. I tell patients about the MRI study in which brain stimulation in medical students led to substantial increase in brain volume; it is a vivid example of active brain plasticity in adulthood.
Almost all Baby Boomers have heard of benefits associated
with doing crossword puzzles, trying new hobbies such as dancing, or engaging in a game of chess.31 I encourage them to take on
hobbies that they enjoy. This approach ensures that they continue with their hobby and adhere to their plans for regular brain
workout. Baby Boomers with challenging careers (e.g., engineers,
doctors, executives, architects) acquire plenty of brain exercise at
work and should not worry about which new brain-stimulating
software to play on their iPod or Nintendo DS. These individuals may benefit more from Tai chi, yoga, or other programs that
combine thinking and concentration with relaxation.
9. Socialize. Several studies reveal the importance of socialization for better brain health and lower stroke risk.60–62 Middle-aged
individuals with isolated lifestyles are more prone to cognitive
decline with aging and dementia.63 Reduced risk of dementia in
individuals who enjoy participating in social activities, volunteering, or spending time with friends has been well documented.
Though understanding the neurobiology of better brain health
due to mingling with others is in its infancy, it is reasonable (based
on observational studies) to recommend participation in social
activities. Joining dance groups may be an excellent strategy to
exercise, engage the brain, and socialize—all at the same time.
10. Beware of depression. Patients who tend to be lonely and
avoid joining social groups may have signs and symptoms of
depression. Such individuals need further evaluation. Depression
may be associated with a smaller hippocampus; some studies suggest that this presumed atrophy can be reversed with antidepressants.64–66 Animal studies support the notion that stress and anxiety may lead to neuronal injury in hippocampus. More studies are
now underway to study the link between depression and dementia, but clearly patients who have major depression need to be
treated promptly. Excessive worrying for memory loss and AD at
a young age may represent signs of untreated major depression.
Stress and anxiety increase stroke risk.67 I remind patients of the
importance of relaxation—and that laughter is the best medicine.
I encourage them to smile more often. Many Baby Boomers are
consumed with so many personal and professional commitments
they forget to laugh. They need to be reminded of the importance
of taking it easy and enjoying life as much as possible.
Improving Brain Fitness
For Baby Boomers, memory loss should not be considered synonymous with early signs of AD. Late-life dementia is a result of
multiple “hits” to the brain, from a variety of risk factors such as
hypertension, obesity, chronic stress, head trauma, OSA, and poor
Practical Neurology
39
AD Prevention
diet. Baby Boomers must realize that they have many opportunities for improving their brain fitness and actually increase the size
of their cortex and hippocampus. Instead of worrying about AD,
they need to establish a strategy to improve blood pressure, sleep,
and medical issues. We must remind them that exercise, challenging brain activities, heart-healthy diet, and laughing more often
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Majid Fotuhi, MD, PhD, is the Director of the Center for Memory and
Brain Health at The Sandra and Malcolm Berman Brain & Spine Institute
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