Research Article
Open Access
A New Public Health Paradigm for Alzheimer's Disease
Research
Mario D Garrett* and Ramon Valle
San Diego State University, California, USA
*Corresponding author: Mario D. Garrett, Professor, School of Social Work, San Diego State University, San Diego, California, USA, 92182-4119, Tel:
(619) 594-2818; Fax: (619) 594-5991; E-mail:
@
Received: July 21, 2015; Accepted: November 18, 2015; Published: December 19, 2015
Citation: Garrett MD, Valle R (2015) A New Public Health Paradigm for Alzheimer's Disease Research. SOJ Neurol 2(2), 1-9. DOI: http://dx.doi.org/10.15226/2374-6858/2/2/00117
AbstractTop
In industrialized countries Alzheimer's disease is becoming a
pandemic. Over the next few decades one in six people are predicted to
have Alzheimer's disease. This will evolve into a public health tragedy.
Unfortunately there is a problem with dementia research. After more
than a century of research we cannot answer basic questions about
the disease, whether the biomarkers are truly the disease or whether
these biomarkers are symptoms of another yet unknown disease.
This paper summarizes the literature to show that there are other
correlates—and possible causes—of Alzheimer's disease that have
not received attention, but if the disease is approached from a public
health perspective, then the disease can be organized under the four
potential integrated processes of Trauma, Penumbra, Perfusion and
Plasticity. Through this re-framing of the disease as a public health
problem an opportunity emerges that can expand and reinvigorate
research in Alzheimer's disease. Such new insights can elucidate a
better and fuller understanding of the disease and provide some real
hope to defining a road map to a cure.
Keywords: Alzheimer's disease; public health; trauma, penumbra, perfusion; plasticity
Keywords: Alzheimer's disease; public health; trauma, penumbra, perfusion; plasticity
Introduction
Alzheimer's disease is evolving as a disease of global
proportions. With life expectancy in industrialized countries
inching up to 85 years, and where one-third of those of this age
are predicted to have Alzheimer's disease [1], it is anticipated
that one in six of the total population of industrialized countries
will have the disease. Alzheimer's disease is maturing into a 21st
century pandemic. But there is a problem. In the last hundred
years of research we have gained very little significant insight
into stopping this disease.
The search for exclusive biomarkers for Alzheimer's disease—a neuropathology that signifies the deterioration of behavior associated with Alzheimer's disease—continues to elude researchers. Alzheimer's paradigm is still too narrowly defined through biomarkers—biological, genetic and chemical— when in the literature there are other factors that are shown to contribute to this disease. The aim of this paper therefore is to highlight alternate interpretations of Alzheimer's disease mechanisms and to readdress why such mechanisms have been left out of the National Institute on Aging-Alzheimer's Association (NIA-AA) 2011 research agenda for Alzheimer's disease [2].
The Amyloid Cascade hypothesis is the dominant theory in Alzheimer's disease [3]. This theory postulates that the deposition of the amyloid-β peptide (plaques) in the brain is a central event in Alzheimer's disease pathology, followed by tau protein deposits (tangles) that clog up the brain causing impaired cognition leading to dementia. As a result of this theory, research on Alzheimer's disease has exclusively focused on neurobiology and biochemistry. This exclusivity was reinforced when the Amyloid Cascade hypothesis was adopted by the 2011 NIA-AA guidelines that concentrate on identifying biomarkers in the preclinical stage of the disease [4].
But research continues to expose anomalies that cannot be easily explained by these guidelines [5,6]. Additionally, there is now a valid and persuasive criticism of the current research methodologies in Alzheimer's disease: the lack of evidence that biomarkers cause the disease; that the disease behaves more as a syndrome with diffuse expression; and that the methodology used to study the clinical aspects of Alzheimer's disease is unreliable and invalid [7-9]. In particular, although the plaques and tangles seem to be more prevalent among people with Alzheimer's disease there are people that live independently and unaware of this neuropathology in their brain [10,11]. While in human clinical trials, patients using experimental drugs that succeeded in removing or inhibiting the development of plaques, showed worse cognitive performance than the controls [12-14].
The problem was then—and is now—that the relationship between the neurobiology and the disease is not distinct. Despite such lack of evidence, the Amyloid Cascade hypothesis remains resilient due to the lack of counter paradigms to challenge its dominance in guiding Alzheimer's disease research [15]. Emerging clinical studies are however taking a more pragmatic approach; showing how lifestyle changes reverses cognitive decline and how other factors are involved in Alzheimer's disease [16,17]. As a result, there is growing support for a broader approach public health perspective to studying the causes and mechanisms of Alzheimer's disease. Under this perspective the seeming disparate processes of Alzheimer's disease can be organized under four related processes of Trauma, Penumbra, Plasticity and Perfusion.
The search for exclusive biomarkers for Alzheimer's disease—a neuropathology that signifies the deterioration of behavior associated with Alzheimer's disease—continues to elude researchers. Alzheimer's paradigm is still too narrowly defined through biomarkers—biological, genetic and chemical— when in the literature there are other factors that are shown to contribute to this disease. The aim of this paper therefore is to highlight alternate interpretations of Alzheimer's disease mechanisms and to readdress why such mechanisms have been left out of the National Institute on Aging-Alzheimer's Association (NIA-AA) 2011 research agenda for Alzheimer's disease [2].
The Amyloid Cascade hypothesis is the dominant theory in Alzheimer's disease [3]. This theory postulates that the deposition of the amyloid-β peptide (plaques) in the brain is a central event in Alzheimer's disease pathology, followed by tau protein deposits (tangles) that clog up the brain causing impaired cognition leading to dementia. As a result of this theory, research on Alzheimer's disease has exclusively focused on neurobiology and biochemistry. This exclusivity was reinforced when the Amyloid Cascade hypothesis was adopted by the 2011 NIA-AA guidelines that concentrate on identifying biomarkers in the preclinical stage of the disease [4].
But research continues to expose anomalies that cannot be easily explained by these guidelines [5,6]. Additionally, there is now a valid and persuasive criticism of the current research methodologies in Alzheimer's disease: the lack of evidence that biomarkers cause the disease; that the disease behaves more as a syndrome with diffuse expression; and that the methodology used to study the clinical aspects of Alzheimer's disease is unreliable and invalid [7-9]. In particular, although the plaques and tangles seem to be more prevalent among people with Alzheimer's disease there are people that live independently and unaware of this neuropathology in their brain [10,11]. While in human clinical trials, patients using experimental drugs that succeeded in removing or inhibiting the development of plaques, showed worse cognitive performance than the controls [12-14].
The problem was then—and is now—that the relationship between the neurobiology and the disease is not distinct. Despite such lack of evidence, the Amyloid Cascade hypothesis remains resilient due to the lack of counter paradigms to challenge its dominance in guiding Alzheimer's disease research [15]. Emerging clinical studies are however taking a more pragmatic approach; showing how lifestyle changes reverses cognitive decline and how other factors are involved in Alzheimer's disease [16,17]. As a result, there is growing support for a broader approach public health perspective to studying the causes and mechanisms of Alzheimer's disease. Under this perspective the seeming disparate processes of Alzheimer's disease can be organized under four related processes of Trauma, Penumbra, Plasticity and Perfusion.
Diagram:
Schematic representation showing an initial
Trauma causing a Penumbra that is moderated and mediated by
Plasticity and Perfusion.
Figure 1:
The Diagram provides a schematic diagram of a model
that defines how these four processes might interact in order
to permit research to understand and examine delaying or
preventing Alzheimer's disease. In this model an initial Trauma
that turns into a Penumbra—an initial cluster of cell death—
which is more likely to grow and cause Alzheimer's disease if the
brain is denied two mediating and moderating factors: the lack of
adequate cerebral Perfusion and reduced Plasticity to assimilate
the Penumbra. Without these moderating factors of Plasticity
and Perfusion, the Penumbra will grow and affect larger areas
of the brain. This broader interpretation of Alzheimer's disease
assimilates both the traditional Amyloid Cascade hypothesis, but
also broadens the scope to address contributing factors that are
emerging in public health.
Trauma
The initial trauma that starts Alzheimer's disease is unknown.
Although most of the research focuses on genetic mechanisms,
there is growing evidence that other, more relevant, mechanisms
exist: viral (HIV/AIDS, herpes simplex virus type I, Varicella
zoster virus, cytomegalovirus, Epstein-Barr virus), bacteria
(syphilis and Lyme-disease/borrelia), parasites (toxoplasmosis,
cryptococcosis and neurocysticercosis), behavior (Alcohol,
cigarette smoking, recreational drugs, concussion/mild/severe
brain trauma) environmental elements (possibly aluminum),
infections (possibly prions such as in Cretchfeldt-Jakobs
disease), vascular causes (stroke, multiple-infarct dementia
hydrocephalus, and injury or brain tumors) and emotional
trauma. There is literature that correlates all of these factors with
Alzheimer's disease, but none of these factors appear in the NIAAA
research agenda for Alzheimer's disease.
Genes
Although there is a growing list of genes that could determine dementia, most cases of Alzheimer's disease are sporadic
and have unknown causes [18]. The Genetic Testing Registry
identifies eleven specific genes that are being studied [19],
but other neurobiological diseases also have the same genetic
markers, such as: Parkinson's disease, Lewy bodies, Cretchfeldt-
Jakobs disease, Huntingdon's disease, Wilson's disease,
Progressive supranuclear Palsy, hydrocephalus, Conti cobesiler
degeneration, multiple scelorisis, Down's syndrome, meta
chronic leucodystropy and space occupying lesions [19]. In terms
of genetic markers, there is no pure type of Alzheimer's disease. It
could be that the disease exists in a continuum, although 'mixed'
dementias are rarely diagnosed as the majority of diagnostic
procedures are psychologically biased toward a diagnosis of
Alzheimer's disease [20].
Viral
As with genetic research, virus infections that specifically and
exclusively cause Alzheimer's disease have not been identified.
But there is growing evidence that viruses are important in
Alzheimer's disease and other neurological disorders [21]. The
primary virus that we know causes dementia is HIV/AIDS. The
cumulative risk of developing HIV-Dementia during the lifetime
of an HIV+ person was 5–20% [22], which is increasing to 38-
40% [23]. HIV-AIDS is also prone to an opportunistic infection
cytomegalovirus that also affects the central nervous system and
can cause dementia independently [24].
Herpes simplex virus type I—non-sexually transmitted— remains ubiquitous [25]. Once infected, the virus remains in the peripheral nervous system and cause encephalitis that affects the same regions of the central nervous system (temporal and frontal cortex, and hippocampus) as those most affected by Alzheimer's disease [26]. Emerging studies [27] report that there is an increased risk of Alzheimer's disease when the virus is present in combination with the genetic marker of APOE-ε4 allele, while independently neither increase the risk of Alzheimer's disease. Similar to the herpes simplex virus type I, the Varicella zoster virus has also been more prevalent among patients with atherosclerotic dementia [28]. In contrast, controls— schizophrenics or patients with other psychiatric disorders or in groups of healthy people—had lower prevalence. Similarly, chlamydia pneumonia infections are found in 90% of Alzheimer's disease patients, with the virus itself found inside the plaques in their brain [29]. These studies are still correlational, but they point out a growing interest in viral infections and how they can cause or promote Alzheimer's disease.
Herpes simplex virus type I—non-sexually transmitted— remains ubiquitous [25]. Once infected, the virus remains in the peripheral nervous system and cause encephalitis that affects the same regions of the central nervous system (temporal and frontal cortex, and hippocampus) as those most affected by Alzheimer's disease [26]. Emerging studies [27] report that there is an increased risk of Alzheimer's disease when the virus is present in combination with the genetic marker of APOE-ε4 allele, while independently neither increase the risk of Alzheimer's disease. Similar to the herpes simplex virus type I, the Varicella zoster virus has also been more prevalent among patients with atherosclerotic dementia [28]. In contrast, controls— schizophrenics or patients with other psychiatric disorders or in groups of healthy people—had lower prevalence. Similarly, chlamydia pneumonia infections are found in 90% of Alzheimer's disease patients, with the virus itself found inside the plaques in their brain [29]. These studies are still correlational, but they point out a growing interest in viral infections and how they can cause or promote Alzheimer's disease.
Bacteria
Alois Alzheimer—who identified the disease in 1907—was
primarily interested in syphilis. For centuries, other than just
old age, syphilis was the main and only known cause of dementia
before Alzheimer's disease was identified. Today, although
neurosyphilis is rare—where the bacteria causes neuropathology
that results in clinical features of dementia—another bacterium
gaining interest is Lyme disease. Lyme dementia has become a
greater concern because it is the most common vector-borne
disease in the northern hemisphere [30]. Since there is no cure for Lyme disease, the expectation is that more patients will
develop Lyme dementia in the near future [31].
Behavior
Alcohol has had a long history with mental health and is
already a public health concern. There has been an increasing
interest in the relationship between a history and heavy intake
of alcohol with Alzheimer's disease. There is now evidence that
this relationship is independent and not mediated by history
of hypertension, cardiovascular disease, or head injury [32].
Meta-analyses studying the relationship between alcohol
consumption and risk of Alzheimer dementia and dementia
reported a 'J' shaped relationship, with moderate drinking
showing moderate protection [33,34]. A history of high alcohol
intake has been shown to increase the risk of Mild Cognitive
Impairment and Alzheimer's disease in a large Canadian study
[35], in a US study [36] and; in a Brazilian study [37]. Excessive
alcohol use may damage the brain due to toxic effects of alcohol,
metabolic changes in the brain, neurotransmitter imbalances and
nutritional deficiency injury [38].
Concussion or mild traumatic brain injuries (MTBI)—incurred through falls, motor vehicle accidents, trauma from explosives, and sports-related activity—account for 75% of all traumatic brain injuries sustained in the United States [39]. MTBI are seen at all ages from youth [40] to adults [41,42]. Sustaining only one or two concussions has permanent neurological repercussions [43] and is known to be risk factors for developing Alzheimer's disease later in life [44-46]. Smoking and secondhand smoking is associated with a 50-60% risk of Alzheimer's disease [47-51], having a dose effect—the more you smoke the higher the risk [52,53]. This is also related to the vascular changes.
Concussion or mild traumatic brain injuries (MTBI)—incurred through falls, motor vehicle accidents, trauma from explosives, and sports-related activity—account for 75% of all traumatic brain injuries sustained in the United States [39]. MTBI are seen at all ages from youth [40] to adults [41,42]. Sustaining only one or two concussions has permanent neurological repercussions [43] and is known to be risk factors for developing Alzheimer's disease later in life [44-46]. Smoking and secondhand smoking is associated with a 50-60% risk of Alzheimer's disease [47-51], having a dose effect—the more you smoke the higher the risk [52,53]. This is also related to the vascular changes.
Vascular
In a review of the literature [54], researchers reported that
stroke is one of the leading causes of disability, Alzheimer's
disease and death in the USA. While many stroke victims improve,
others worsen. Three months after a stroke, 25-33% of patients
express Alzheimer's disease, and an even greater proportion
have severe cognitive impairment [55]. Stroke doubles the risk
of Alzheimer's disease even after adjusting for age, sex, education,
and exposure to individual stroke risk factors [56]. With over
790,000 victims of stroke each year in the United States, it is an
important etiology of Alzheimer's disease that is often neglected
in research.
Environmental
Epidemiological studies suggest that there is a link between
metal, especially aluminum and Alzheimer's disease. Aluminum
may not be as innocuous as once thought since it may actively
promote the onset and progression of Alzheimer's disease [57],
as a form of chronic aluminum neurotoxicity [58]. Although
rare nowadays, it was first described among dialysis patients
[59] where aluminum acted as a neurotoxin trauma that caused
Alzheimer's disease [60].
Similar to plaques and tangles—misshapen amyloid and tau proteins that clamp together—a novel form of human prion disease is linked with bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob's disease [61]. The hallmark of prion disease is the accumulation of misfolded protein that is toxic to neuronal cells [62].
Similar to plaques and tangles—misshapen amyloid and tau proteins that clamp together—a novel form of human prion disease is linked with bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob's disease [61]. The hallmark of prion disease is the accumulation of misfolded protein that is toxic to neuronal cells [62].
Emotional
Adverse childhood experiences start a cascade of risk
behaviors that are associated with enduring changes in the
nervous, endocrine, and immune systems [63]. In a Californian
study of 1116 elderly community residents, self-reported
cognitive function was lower than expected for those who had
experienced sustained economic hardship, even after adjusting
for age, sex, and co-morbidity [64]. Poverty, larger family size
and urban residence were associated with increased Alzheimer's
disease risk [65]. Some adverse childhood events continue to
have a negative effect on later-life cognitive performance on some
people, while others seem immune, underlying the necessity to
consider events individually and not as global test scores [66].
All these variables—genetic, viral, bacteria, behavior, environmental, vascular, and emotional—act as a trauma, a shock, to the brain, affecting the brain independently or in combination. There might be other traumas that are as yet unidentified. But once there is a trauma to the brain, then the body reacts in a very specific way. Researchers a century ago reported that there was a shadow, a halo that follows from a trauma. Clinically, this is referred to as a penumbra. There are indications [67] that although the origins of the trauma in Alzheimer's disease are undefined, the process suggests that cell death extends beyond the region of damaged tissue. Trauma results in an initial assault of cell death followed by a penumbra a broader cluster of neuronal death.
All these variables—genetic, viral, bacteria, behavior, environmental, vascular, and emotional—act as a trauma, a shock, to the brain, affecting the brain independently or in combination. There might be other traumas that are as yet unidentified. But once there is a trauma to the brain, then the body reacts in a very specific way. Researchers a century ago reported that there was a shadow, a halo that follows from a trauma. Clinically, this is referred to as a penumbra. There are indications [67] that although the origins of the trauma in Alzheimer's disease are undefined, the process suggests that cell death extends beyond the region of damaged tissue. Trauma results in an initial assault of cell death followed by a penumbra a broader cluster of neuronal death.
Penumbra
Perusini made an interesting early observation that: 'The glia,
then, develop around the deposits and encapsulates them just as
they usually do with every foreign body (in the broadest sense)'
[68] (p121). Such an interpretation suggests that the growth of
plaques could be a protective response, where the initial toxic
trauma is enveloped into harmless mass by other cells [69].
Singular or multiple traumas—like a stroke—kill off a significant
number of neurons and, in response the brain protects itself with
an envelope of white cells (glial) transforming the toxic clump
inert. To some degree, this happens all the time. The brain is in
constant state of change. Alois Alzheimer himself identified this
penumbra as a halo, or a shadow: 'Sometimes there are also rodlike
cell elements of obvious glial origin lying in the halo' [70]
(p80). The dual nature of this process—where the damage is
quarantined and contained, while in other cases there is a further
shockwave of neuronal death beyond the initial trauma—is an
enigma. Two possible moderators of this spread of the penumbra
is cerebral plasticity—potential for neurons and glial cells to
grow; and perfusion—blood flow in the brain that provides the
energy-hungry neurons the necessary nutrients, required to
function and repair themselves.
Plasticity
Within a public health approach, one of the moderating or
mediating factors that affect the development of Alzheimer's
disease is Plasticity. Although the brain naturally shrinks with
age, brain atrophy in Alzheimer's disease is five-fold higher
during 7–10 years of the disease, translating to approximately
200–400g of brain mass loss [71]. Such loss is in addition to the
plaques and tangles [72]. But there is a process that counteracts
this loss. Ernesto Lugaro in the early 1906 was responsible for
introducing the term plasticity into neuroscience [73]. Lugaro
refers to 'psychic plasticity; plasticity of the neurons; plasticity
of the neurofibrils' a process that continues throughout life
in order to establish new connections between neurons [74].
Such development is apparent in maturation, learning and even
functional learning after brain damage throughout the lifespan
[75]. In some cases neuronal growth takes place on a daily basis
[76]. A growing body of evidence is exposing the capacity of
the brain to regenerate throughout lifespan through education
[77,78].
Education
In the now famous Nuns' Study [79] Snowdon found that
8% of the nuns who had the most severe level of neurological
disease in their brain behaved and acted free from dementia. The
researchers explained this finding by arguing that education is an
important moderating factor [79]. There seems to be an inverse
dose-response relation between education and Alzheimer's
disease [80], with education acting as a proxy for cognitive reserve
[81]. Education might not only increase capacity and plasticity
but might also modify behavior away from risk behaviors that
promote Alzheimer's disease [82].
Dancing/Music/Body Movement
The power of music and dancing—including other social
activities—correlate with positive gains in cognitive tests.
Institutionalized older adults improved faster than communitybased
participants in studies that promoted music, dance,
singing, food preparation, and selecting pictures [83]. The
results may be more than just exercise and social engagement,
although the exact mechanism is unknown [84]. In a now classic
longitudinal study [85] looking at the frequency of participation
in leisure activities and physical-activity, after a follow-up period
of 5.1 years only reading, playing board games, playing musical
instruments, and dancing were associated with a reduced risk
of Alzheimer's disease and vascular dementia. Because these
activities were studied in addition to physical activity, they
provided an additional benefit to cerebral perfusion. Numerous
studies have measured brain volumes of professional pianists,
reporting that the more hours a musician played the more heavily
myelinated or tightly packed their white matter axons were [86].
Such changes might also be specific to the type of learning, so that
white matter architecture differs between musicians and nonmusicians
[87].
Brain Exercises
The utility of cognitive training programs in delaying cognitive decline has gathered momentum since the first large
randomized controlled double-blind trial using a commercially
available cognitive training program [88,89]. The two most
widely cited ongoing studies are ACTIVE and IMPACT [90,91].
Even patients with early to moderate Alzheimer's disease using
computer exercises had better performance on cognitive tests
[92]. Gains were recorded in standardized measures of memory
and attention ten years after the intervention, on tests that were
not part of the initial intervention [93]. Since there was growth in
the hippocampus these benefits seem to involve brain plasticity
[94]. The idea that interacting with the environment continues to
regenerate and change the brain throughout life—both positively
and negatively—supports the hypothesis that brain plasticity
offers a possible mediating mechanism through which the
brain might be provoked to repair itself [95]. Cognitive training
programs, music and dancing have been associated with brain
growth [94.96], and such plasticity/neurogenesis seems to delay
the onset of Alzheimer's disease [97,98].
Cerebral Perfusion
The fourth process in this public health model is Perfusion—
blood flow to the brain. At autopsy, 60–90% of patients with
Alzheimer's disease exhibit variable cerebrovascular pathology
and almost 30% show evidence of cerebral infarction [99,100].
As part of a multistage theory of Alzheimer's disease, having the
necessary blood flow to the brain is a linchpin of a healthy brain.
Evidence is mounting that vascular risk factors launch a cascade
of cellular and molecular changes that initiate cognitive deficits
and eventual progresses to Alzheimer's disease [101]. There is a
strong indication that there is an association between diminished
(hypo) perfusion and Alzheimer's disease. Cerebral perfusion is
a balance that must be maintained within narrow margins. Too
little pressure causes brain tissue to become ischemic—shortage
of oxygen and glucose needed for cellular metabolism—while
too much pressure causes cellular damage. Cerebral perfusion is
closely aligned with vascular dementia. Although the brain is only
2% of the body weight it consumes 15-20% of all cardiac output
and 20% of all oxygen in the body. Such balance is maintained
by complex mechanisms, and one such mechanism—through
vasoconstriction and vasodilation—is temperature [102].
Temperature
Perhaps not surprisingly, older adults have slightly lower
body temperatures than younger adults [103]. Average
temperature for older adults is 97.7°, lower than the 98.6°
F benchmark. Although a systematic review reports great
variance in temperature across gender and individuals, making
aggregate statistics unreliable predictors [104]. Biologically, a
lower temperature seems to enhance longevity. In the Baltimore
Longitudinal Study of Aging, men with a core body temperature
below the median lived significantly longer than men with body
temperature above the median [105]. However the contradiction
is that lower temperature might also results in lower perfusion.
The association of age with Alzheimer's disease might be
mediated by decrease in body temperature, an avenue of research
that remains untapped.
Activity
Perfusion can also be controlled by activity. Being active
enhances the blood flow to the brain. In a four-year longitudinal
study [106] retirees who elected to become physically inactive
exhibited significant decline in perfusion while those who
continued to work or engage in regular activities maintained
more constant perfusion levels. Interestingly, the relationship
between perfusion and cognition was acknowledged when
the researchers reported that active retirees scored better
on cognitive testing after a four-year follow-up. Blood flow to
the body is important for all organs, including the brain. Being
physically active has been shown to decrease the incidence or
delays the onset of Alzheimer's disease [107,108],[94]. So much
so that Alzheimer's disease can be defined as a 'diseasome of
physical inactivity' [109], where activity delays such risks [110].
General Anesthetic
The most common sudden hypo perfusion occurs under general
anesthetic [111]. Evidence for anesthesia-induced neurotoxicity is
mounting suggesting that general anesthetics may be neurotoxic
to both young and aging brains [112]. In a population of healthy
elderly patients, undergoing non-vascular abdominal surgery
[113] cerebral desaturation—an indication of hypoperfusion—
occurs in one in four patients. When this happens, those patients
have higher incidence of early postoperative cognitive decline
and longer hospital stay. Maintaining a consistently healthy
cerebral perfusion is important to brain health. It would be
informative to see changes in the penumbra of stroke patients
who undergo general anesthetic, an avenue of research that still
needs to be undertaken. There are many similarities between
vascular dementia and Alzheimer's disease. Something that even
Alzheimer entertained: 'The question is: are these cases to be
assigned to Dementia senilis or to arteriosclerosis? …Perhaps
this arrangement of atrophy could be related to the vascular
supply of the temporal lobe.' [70] (p97). Since vascular dementia
is the second largest category of dementia it is important to
address the relationship and difference. Alzheimer's disease and
vascular dementia are the two most common forms of dementia,
sharing many common medications, pathological, symptomatic
and neurochemical features [20].
Discussion
The public health model described and presented in this
introduction defines how four processes might interact to
generate or possibly retard or delay Alzheimer's disease. An
initial Trauma that turns into a Penumbra is more likely to
cause Alzheimer's disease if the brain is denied two mediating
and moderating factors: a lack of adequate cerebral Perfusion,
or if there is a lack of Plasticity. Without these two factors the
penumbra will grow and affect larger areas of the brain—and
such damage will go beyond plaques and tangles. This broader
public health interpretation of Alzheimer's disease assimilates
both the traditional Amyloid Cascade hypothesis [3] and
broadens the scope to include emerging research in the public
health arena, some of which were introduced in this paper.
More importantly, these mechanisms also address the mounting anomalies in Alzheimer's disease research. There is more than
one trauma that results in similar outcomes. The initial trauma
might result in a penumbra which might or might not progress.
The neurological disease might or might not affect cognition.
These multiple pathological mechanisms—that all inter-relate—
have not been explored comprehensively. A healthy lifestyle—
and the effect this has on cerebral perfusion—has been shown
to delay Alzheimer's disease. There is also a century of work that
looks at how learning and education seems to have a protective
influence against Alzheimer's disease—plasticity, neurogenesis
and capacity can delay, protect, and recover—even after a major
trauma like a stroke [114]. Older age does not necessarily lead
to Alzheimer' disease. When Henrikje van Andel-Schipper died in
2005, she was the oldest woman at age 115, and in post-mortem
examination her brain showed no signs of neuropathology [115].
It seems some people escape dementias. Long-lived older adults
escape or delay dementias because they maintain adequate
perfusion, have functional plasticity and have evaded major
traumas [116].
Without a broader a public health approach dementia research will remain confined within research silos away from any chance of rich crosspollination. But within this public health a more nuanced approach to the many different types of dementias can be explored. Different causes of the many types of dementias might hold unique insights into their unique cures [17]. Of equal importance is to examine how most older adults escape Alzheimer's disease, an approach that can be promoted within a public health, rather than within a disease-model.
Without a broader a public health approach dementia research will remain confined within research silos away from any chance of rich crosspollination. But within this public health a more nuanced approach to the many different types of dementias can be explored. Different causes of the many types of dementias might hold unique insights into their unique cures [17]. Of equal importance is to examine how most older adults escape Alzheimer's disease, an approach that can be promoted within a public health, rather than within a disease-model.
Conclusion
By accepting the evidence of possible external traumas (viral,
bacterial, biological, chemical, environment, behavioral) that
can initiate Alzheimer's disease, and then assigning importance
to the role of perfusion and plasticity to delay the growth of the
penumbra, this approach reframes the disease as a public health
issue with potential public health solutions. Such a methodology
will include educational as well as legislative programs that
reduce and lower the exposure to traumas. Reduction of
concussions (in sport, military, recreational activities) should be
made a priority. Programs that educate on the effects of smoking
and heavy drinking on the brain will need to be promoted, as
well as programs that address environmental toxicity both in the
air and in our water. For perfusion, increasing activity provides
an incentive for families to promote daily activity among adults
of all ages. City walkability programs, and social engagement
programs all promote walking, swimming, light exercise,
gardening among other activities. The family's role remains
central in improving plasticity since engaging patients in social
activities, dancing, music and other cognitive exercise will have
both protective factors as well as showing promise of reversing
the attrition from the disease. Such pragmatic approaches have
already been shown to be efficacious [16]. Adjusting the focus to
include environmental and social components brings the disease
squarely into the public health arena where a broader array of
scientists, academics and clinicians can break down research silos
and actively work together to address the emerging pandemic of
Alzheimer's disease.
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