Behavioural Brain Research 334 (2017) 163–177

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Behavioural Brain Research

journal homepage: www.elsevier.com/locate/bbr

Review

Cognitive behavioral therapy (CBT) for preventing Alzheimer’s disease MARK

⁎
Larry D. Reid, Faith E. Avens, Alicia A. Walf
Department of Cognitive Science, Rensselaer Polytechnic Institute, Troy, NY, USA

A R T I C L E I N F O A B S T R A C T

Keywords: This review provides the rationale for implementing cognitive behavioral therapy (CBT) for the prevention of
Behavior Alzheimer’s disease (AD). There are known risk factors associated with the development of AD, some of which
Prevention may be ameliorated with CBT. We posit that treating the risk factors of inactivity, poor diet, hyposmia and
Olfaction anosmia, sleep disorders and lack of regularly engaged challenging cognitive activity will modify the physiology
Sleep
of the brain sufficiently to avoid the accumulation of excess proteins, including amyloid beta, causal events in
Inactivity
the development of AD. Further, the successful treatment of the listed risk factors is well within our technology
Cholesterol
Computer games to do so and, even further, it is cost effective. Also, there is considerable scientific literature to support the
Fluid flow proposition that, if implemented by well-established practices, CBT will be effective and will be engaged by
those of retirement age. That is, we present a biologically informed CBT for the prevention of the development of
AD, i.e., an aspect of applied behavioral neuroscience.

1. Introduction For example, PubMed (the search engine of the US National Library of
Medicine) tabulates and lists articles germane to AD. In 1971, there
Those who are at retirement-age (middle 60s) can expect to live for were 11 articles on AD. In 1981, there were 161. During the 80 s and
another two decades, a goodly portion of a life-time (actuarial data, beyond, there has been a steady yearly increase in articles on AD; and in
USA Social Security Administration). Those decades can be and often 2016 there were over 9000. As of early 2017, Pub Med has listed over
are very satisfying. However, those decades are marred by fear of de- 123,000 articles relevant to AD.
veloping Alzheimer’s disease (AD). AD is horrible, insidious, currently The extensive research on AD has yielded considerable knowledge.
incurable and extremely costly in terms of palliative care. Retirees fear Much of the modern understandings of AD are embedded in the amy-
the loss of mind and the helplessness of advanced AD, and rightfully so. loid beta (Ab) theory of AD [1]. The Ab theory holds that a metabolic
Epidemiological data confirm what retirees have observed: about product of neuronal activity, the protein Ab, is causally related to the
30–50% of those living to their mid–80 s will have suffered a marked degeneration of neuronal tissue. There are various theories of how ex-
loss of cognitive ability, a harbinger of advanced AD, or will have actly Ab becomes toxic, but it seems clear that an accumulation of Ab in
suffered advanced AD. Further, the tragedy of AD affecting loved the interstitial fluid of the brain is associated with a process that leads
partners takes an enormous toll on their healthier partners. to an insidious loss of brain tissue. Further, it is posited that when Ab
Observations at autopsy, and now with the aid of modern brain- accumulates in the fluid of the brain that it tends to combine with other
scan-technology, confirm that the behavioral manifestations of ad- proteins, including other molecules of Ab, to form large globs of pro-
vanced AD are due to a massive loss of brain tissue. The loss is so ex- teins (amyloid plaques). The plaques induce immune processes that do
tensive that no one can apprehend how to restore the loss. This fun- not always succeed in removing them. The presence of large plaques
damental fact implies that the only hope for dealing with AD, other and the induced inflammatory processes (i.e., accumulation of micro-
than palliative care, is to prevent its advancement. Stated differently, glia and release of cytokines) likely contribute, in some way (probably
treatments designed to correct end-stages of the disease are probably interfering with blood flow near or in capillaries), to the toxicity
too late. leading to cell-death [2–6]. The debris of cell-death contributes to
Given the gravity of AD and the realization that a large proportion further accumulation of proteins and further toxicity. There are im-
of the population of prosperous nations is approaching retirement-age, portant implications that can be drawn from this summary of a version
research directed toward understanding and treating AD has increased. of the modern Ab theory of AD. We will attend to those implications

Abbreviations: AD, alzheimer’s disease; Ab, amyloid beta; B-NC, brain-nasal cavity; CBT-I, cognitive behavioral therapy for insomnia; FINGER, finnish geriatric intervention study to
prevent cognitive impairment and disability; LOAD, late onset AD; MCI, mild cognitive impairment; LDL, low density lipoprotein; HDL, high density lipoprotein
⁎
Corresponding author at: Dept Cognitive Science, Carnegie Bldg 304, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
E-mail address: [email protected] (A.A. Walf).

http://dx.doi.org/10.1016/j.bbr.2017.07.024
Received 30 May 2017; Received in revised form 15 July 2017; Accepted 18 July 2017
Available online 23 July 2017
0166-4328/ © 2017 Elsevier B.V. All rights reserved.
L.D. Reid et al. Behavioural Brain Research 334 (2017) 163–177

subsequently. 2. Loss of cognitive skill is both a risk factor for the development
The salient symptom of advancing AD is a progressive cognitive of AD and an index of the progression of AD
decline, measurable by psychological tests [7,8]. Also, modern tech-
nology allows assessment of features of the brain such a morphology There has been considerable research associated with the identifi-
and direct counts of amyloid plaques [9]. Psychological testing and cation of risks associated with AD. There is a search for a reliable early
brain-scans both support this conclusion [9]. The process that is AD sign of the progression of the disease to assess the utility of a medicine
probably begins as early as 10 or more years before full dementia is or procedure to treat AD. Also, there is an interest in treating the risks to
present [1]. Further, the time between dementia and death can last see if such would halt the progression of the disease, even in its earliest
months and even years. Hence, AD is a progressive, slowly developing stages. Treating risks, however, has not been explored as extensively as
(but accelerates toward the end) disease. Consequently, there is a warranted by the prevalence and severity of AD.
possibility of halting the progression. Further, the conclusion can be Many individuals of retirement ages have a subtle change of cog-
drawn that the earlier one might attempt to halt the progression, the nition, being noticeable with some forgetfulness. If the losses are not
more likely that a potentially salutatory intervention will, indeed, be sufficient to disrupt the routines of an earlier time, this change is la-
salutatory. beled: age-related cognitive decline. Sometimes this initial cognitive de-
In addition to developing advanced amyloid theories of AD, two cline progresses sufficiently to be manifest as a preclinical stage (mea-
additional advances are salient. They are (a) the understanding that the surable by sensitive cognitive tests) heralding a more problematic stage
brain is considerably more plastic than previously recognized and that labeled mild cognitive impairment (MCI). MCI can be readily measured by
plasticity extends even to advanced ages [10,11], and (b) although standard tests of cognition. Further loss of cognition, including a pro-
limited, there is neurogenesis in the adult brain, even aged brains [12]. found loss of memory, is labeled dementia, the most common of which is
Note that the term plasticity has two meanings. One meaning is the advanced AD (obvious by even casual observation). The process from
same as ordinary learning involving events at synapses. The other, more age-related cognitive decline to dementia and eventually death is con-
common meaning, is related to the observations that consistent activity sidered a continuous process taking a decade or more [8].
not only involves learning in the traditional sense but actually molds A slow, but steady loss of cognitive ability is not only a risk for
the anatomy and general physiology of the brain enabling better per- progression to dementia; it is the major symptom of AD. Periodic tests
formance at that consistent activity. sampling facets of cognitive ability, particularly of memory (and per-
Brain plasticity is most apparent as we mature; a brain is organized haps most salient, episodic memory [16]), will surely track the pro-
by the challenges of learning to walk, talk and think abstractly. gression of untreated AD. A single measure of cognitive ability, how-
Plasticity is apparent as we witness the extraordinary skills of experts as ever, may not be revealing, because a number of temporary factors can
they perform their beyond-ordinary skills in the arenas of art, hobbies, influence any given day’s test-results. Furthermore, pathologic features
entertainment, sports, commerce and academia. These new under- of brain-scans and psychological tests indexing loss of cognition are
standings of the brain have important implications. For example, we concordant with one another [17]. For example, it has been known for
have new treatments for brain-damage. Now, we aspire to restore lost decades that the hippocampus, a large segment of the limbic system
functions rather than, as we did before, merely provide palliative care. (i.e., the olfactory brain, rhinencephalon, or paleomammalian brain) is
A tenant of the modern concept of brain plasticity is that persistent critically involved in memory. In advanced AD, the space formally
activity of a particular kind organizes the brain for efficiency at that occupied by the hippocampus is literally a hole filled with fluid. Fur-
persistent activity. Colloquially, practice makes perfect; and, the es- ther, measurements of the size of the hippocampus are related to stages
tablishment of habits allows the efficient, nearly unconscious, execution of memory loss [18]. For example, those suffering MCI have shrunken
of daily behaviors [13]. Although established as a result of apparently hippocampi [18,19].
utilitarian consequences, habits often have, in the long run, aversive Given that variations in measures of cognition reflect the anatomical
consequences. A basic idea is that regularly engaged activity is a means and physiological status of the brain, the conclusion is: Any treatment
for modifying the brain for health as well as ill-health (establishing preventing the steady decline in cognition often observed as one ages
lifestyles amenable to health or disease). Much of what is modern (measurable by periodic testing with well-developed psychological tests
cognitive behavioral therapy (CBT) is involved with attempts to modify of cognition) will be a treatment preventing AD. Further, any measur-
habits of cognition and behavior which are not useful and often pro- able differences seen between those who age with sound cognition
blematic. compared to those whose cognition is steadily declining are of parti-
Given that: (a) AD is currently not curable. (b) AD develops slowly, cular interest in learning how to prevent AD [15,19].
hence may be preventable. (c) Ab is involved with the development of
AD. (d) Brains remain plastic even to very old age. (e) Modification of 3. Inborn risks for the development of AD
brain in old age follows the same principles as when young; that is,
activity (whether it be cognitive behavior or gross behavior, both being Aging and sex are two well-established risk factors for developing
simultaneously manifestations of the full physiology of a living being) AD. Clearly, the older an individual becomes, the more likely that they
modifies brain, hence shaping the brain for reactivity with future cir- will suffer AD [14,20]. A number of theorists seem to imply that aging
cumstances. And (f) not all persons develop AD as they age, i.e., from causes AD (via a variety of mechanisms, e.g., [2,21–24]). Although the
30 to 50% suffer AD if they live to their mid–80 s [14] while the others concept of aging reflects events which are real, it is not a nuanced
retain their matured cognitive abilities well into advanced ages [15]. It concept. The proposition that AD is caused by aging surely does not, by
follows, we contend, that AD can be prevented by attending to activities itself, explain in any detail why about a third (maybe more) of the ci-
of the elderly, i.e., by CBT for AD. It is one thing to conclude that tizens who reach the age of 85 are stricken with MCI or advanced AD
modifying activity among those of retirement age can prevent AD, a whereas the other proportion is not [14]. If one lives long enough, AD,
generalization so broad and vague as to be almost meaningless. It is or something like it, may eventually be inevitable. However, the per-
another thing to discover exactly what kind of activity might effectively spective guiding research is that it is good to postpone any putative
halt the progression of AD. Also, once a salient or causal variable is inevitability as long as possible (i.e., it would be good if brain-health
identified (or a few salient and causal variables), there is still the issue outlasted bodily health). The observation that aging is highly related to
of how to develop treatments that are practical enough to be widely AD is useful because it may lead to a variable that accounts for why
implemented. aging for some leads to AD while for other it does not [15].
The same line of thinking is applicable to the concept relating sex to
AD. Readers are referred to recent reviews detailing the role of sex and

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steroids for AD [25,26]. In brief, AD is more prevalent among women important functions of cholesterol in the brain is the formation of
[14,25]. Until one specifies the critical differences between men and steroids (neurosteroids). There is a functional role of brain-derived
women that increase women’s risk for AD, knowledge of the greater cholesterol for cognitive processes [36]. Indeed, a controversial and not
prevalence of AD among women is interesting but, by itself, of little yet entirely understood consequence of cholesterol-lowering drugs, like
value. However, the actions of cholesterol and cholesterol-based ster- statins, may be to alter these key glial and neuronal processes and
oids (e.g., sex and stress steroids) may be a potential target that war- thereby alter cognitive function or risk for AD [37,38]. Schreurs [36]
rants further investigation [25]. As one might expect there are sig- citing a large number of studies concluded that high serum cholesterol
nificant interactions between age and sex and propensity to develop levels were related to reduced cognitive ability, MCI and AD (as well as
AD, i.e., being old and female is riskier than being only old or female. cardiovascular disease). However, there are studies indicating that
Indeed, women diagnosed with AD more rapidly experience diminished among persons of retirement age that high cholesterol levels may sus-
cognitive functions and neuropsychiatric status compared to men di- tain cognitive ability. Interestingly, serum cholesterol does not cross the
agnosed with AD [27,28]. Unless one specifies what it is about aging blood-brain barrier. Further, the brain (glia in adults) synthesizes
and sex that is critical, then positing these two interesting variables as cholesterol meeting the CNS’s high demand for cholesterol [36]. Re-
special circumstances in the development AD is merely a setting con- cently, Schreurs and colleagues showed that 27-hydroxycholesterol (a
dition for further research. Fortunately, knowledge from advancing breakdown product of cholesterol) crosses the blood-brain barrier.
research (e.g., specifying the products of certain genes) is specifying Further, when there is a high cholesterol diet, 27-hydroxycholesterol is
functionalities associated with aging and sex that may be causally re- increased in the hippocampus where it is associated with the char-
lated to the development of AD. acteristic signs of AD including cell death. Of further interest is that 27-
There are two developmental tracks for the development of AD: (a) OHC is an endogenous estrogen modulator which in turn led to the
the very rare one, the early onset form which manifests in the hypothesis that diet-induced hypercholesterolemia might disrupt es-
mid–30 s years old and which develops into dementia by late 40s, and trogenic neuroprotection [39].
(b) the more prevalent one that manifests in individuals of retirement In recent years, there has been a renewed focus on the role of
age and beyond. The development of both early and late onset AD leads cholesterol metabolism for AD. This has been partly spurred by the rich
to a massive loss of brain tissue, hence produces similar behavioral animal literature showing that genetic models of AD, which overexpress
changes, e.g., eventually complete loss of memory and becoming genes associated with AD, have altered cholesterol metabolism in as-
helpless. sociation with Ab deposition, cognitive function deficits, and changes in
The early onset AD is common in a town, Yarumal, in the district of affective behaviors (all which mimic what is observed in people with
Antioquia, Columbia and it clearly affects a large number of those who AD) [25,26,40–43]. For example, mice with the APPswe and presenilin
share a common ancestry. Research has identified genetic mutation overexpression have evidence of altered cholesterol, i.e. greater turn-
conferring a very high risk of developing AD among young citizens of over as measured by cholesterol/steroid levels and enzymes responsible
Yarumal [29]. The consequences of inheriting the risky genetic profile for this in key brain structures, such as the hippocampus and prefrontal
for early-onset AD are physiological processes leading to an accumu- cortex [25]. Readers are referred to a recent review describing the
lation of Ab [4,29]. That is: the mutations in the genes for the human translational work in support of a role of cholesterol metabolism, in-
amyloid precursor protein and the enzymes cleaving the protein (se- cluding steroid synthesis in the brain, for AD [25]. Indeed, among
cretases) generate elevated levels of the Ab, which eventuates in excess people with AD, a correlation between high cholesterol levels in cir-
Ab and Ab plaques [1]. It follows from that general conclusion (em- culation and cognitive impairment has been reported [44,45]. As well,
bedded in modern Ab theories of AD) that treatments slowing the ac- lower levels of cholesterol-based neurosteroids, such as allopregnano-
cumulation of Ab, among those carrying the genetic mutation, might be lone, has been proposed as an early biomarker of AD [46]. The role of
therapeutic. Also, treatments facilitating a greater rate of removal of Ab cholesterol is an important consideration given sex differences in AD,
might also be beneficial [30]. described above, that may be related to differences in cholesterol me-
The mutation characteristic of early onset AD is not common among tabolism. As well, these differences in circulating cholesterol levels may
those who develop AD at retirement age and beyond. Like other dis- be associated with poor clearance of Ab and neurotoxic effects [47]. It
orders with several symptoms, it would not be expected that late-onset is important to further understand these links between cholesterol
AD (LOAD) risk is only due to a single gene; there are likely several transport, metabolism, and general homeostasis in the brain with aging,
genes, and their many alleles, involved. As an example, another genetic and risk and progression of AD.
factor is related to developing AD is the ApoE gene. Interestingly, ApoE Knowing the genetic risks associated with early- and late-developing
variants which seem to confer greater risk for development of LOAD are AD has allowed further characterization of the physiology related to
less determinant than the variants of early onset AD [31]. The function those profiles. An advantage of knowing the genetic risks of developing
of ApoE is to transport cholesterol in the circulatory system as well as AD is that further research can specify the proteins produced by the
the brain. As it relates to LOAD, human alleles of ApoE seem to have salient genes. That knowledge will be helpful in specifying the phy-
different roles; some may be protective (ApoE2), others confer risk siological processes usually maintaining the health of neuronal tissue.
(ApoE4) or produce no differences (ApoE3) [32,33]. For example, Of course, that knowledge will also be critical to understanding the
about 50% of individuals that are diagnosed with LOAD, carry the failures to maintain healthy neuronal tissue. For example, the study of
ApoE4 allele compared to about 15% of the general population [32,34]. early-onset AD (familial AD) provides support for the hypothesis that,
The product of the APOE gene is a protein associated with the transport with familial AD, it is excessive production of Ab that overwhelms the
of cholesterol throughout the circulatory system [15]. Knowledge of the capacity of the usual way of clearing metabolic products, particularly
protein produced by the APOE gene leads to the conclusion that fea- Ab, from the brain. With respect to LOAD (sporadic AD), a hypothesis is
tures of cholesterol homeostasis might be significant in sustaining that it is a failure to regularly clear the ongoing production of Ab that
brain-health. In sum, genetic risk alone, or a specific genetic by sex leads to an accumulation of Ab [48]. In both forms of AD, the idea is
interaction, is not sufficient to contribute to the majority of AD cases. that it is a failure to maintain homeostasis with respect to metabolic
What is important here is that cholesterol links these two general products of neuronal functioning that is critical to the development of
classes of inborn risks and is a potential target for therapy. AD. This has given rise to a number of ideas about how to modify the
Cholesterol is an important target to consider. The brain is con- resulting physiologies with respect to halting the development of AD.
sidered to be “cholesterol-rich” (or contains 25–30% of the entire vo- For example, it is posited: an accumulation of metabolic products in the
lume of the body’s cholesterol) [35]. The primary use of cholesterol in brain, whether it be Ab or 27-OHC, is germane to the development of
the brain is oligodendrocytes’ production of myelin sheaths. Other AD. That, in turn, leads to a focus on fluid flow within the brain; in as

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much as, such flow might regularly clear the excesses from interstitial involving 42 studies and 3781 older adults [59] supports the conclusion
fluid [21]. There are other risks associated with the development of AD, that aerobic fitness training enhanced or sustained cognitive ability
and they may also affect the development of AD. with small to moderate effect sizes. Also, other reviews of preventable
risks indicate that regular exercise will likely delay the onset of full-
4. Other risk factors (other correlates) of developing AD blown dementia [60–63].
Ethell [21] suggested that because intracranial pressure forces the
There is an extensive longitudinal study done in Finland (the flow of fluids through the cribriform-foramina, any event that might
Cardiovascular Risk Factors, Aging, and Dementia study, CAIDE) enhance optimal pressure, hence the optimal flow of cerebral spinal
studying potential risk factors for age-related ill-health including de- fluid (CSF) throughout the brain would aid and abet efficient removal
mentia. That assessment [49] indicated that obesity at midlife, plus of excess Ab. Citing research [64–66] showing that sedentary lifestyles
vascular risk factors (high systolic blood pressure and high total cho- risk the progression of AD, Ethell [21] implied that exercise would fa-
lesterol level) were significant risks for later dementia. With the re- cilitate healthy CSF-flow, hence be therapeutic.
cognition of the results of the CAIDE study, the medical records and Advising and prescribing daily exercise to an elderly, inactive in-
survey data of participants in a large health care system were assembled dividual, however, is usually not sufficient for that person to engage in
[50]. Data on midlife health and subsequent signs of dementia in- health-sustaining exercise. A potential beginning of a program of reg-
cluding AD were available. As with the CAIDE study, being somewhat ular exercise that is boring (and, perhaps even, embarrassing) and
older (within the boundaries of midlife, i.e., older than 53), having a leaves the individual tired and sore is likely to be the of end the pro-
large body mass index (>30 kg/m2), having a high cholesterol level gram. Rather than a “no pain, no gain” perspective, an alternative is
(>251 mg/dl), and high systolic blood pressure (>140 mm/Hg) were more likely to succeed. The better approach is to encourage less intense
risks for dementia and AD during post-retirement ages. Interestingly, activity, but more regular daily activity more compatible with the el-
adding new measures to a salient model of risk for dementia such as derly, inactive citizen. Further, the general approach should be to start
depressed mood, diabetes mellitus, head trauma, poor lung functioning with modest goals and slowly increase the intensity and duration of
and smoking did not add much, if any, to the derived model of risk for exercise, in small achievable increments. Walking has been suggested
dementia and AD [50]. with the goal of eventually attaining 10,000 steps a day.
Within the context of the CAIDE program, there is the Finnish One research program attempted to reduce the costs of treatment for
Geriatric Intervention Study to Prevent Cognitive Impairment and inactivity by using a video presentation followed by a group discussion.
Disability (FINGER) [51]. That study tested the idea that if risk factors This rather brief, remarkably cost-effective intervention, did reduce
for AD were attended to for 2 years, and hopefully modified for the sedentary behavior [67]. To achieve reinforcements for incrementing
better, that such would delay the onset of cognitive decline, the pre- activity, motion-capturing technology can be used to enhance activity
eminent sign of advancing AD [51]. All participants were judged to be and use video-game-like situations to sustain interest, i.e., make use of
at risk for AD. In the intervention group, the risk factors attended to the technology of exergaming [68]. Modern treadmills and stationary
were exercise (actually change from a sedentary lifestyle), diet, vascular bikes can be used to increment the number of “steps” taken while
risk monitoring, and cognitive training. A control group received only making the walking or biking interesting [69]. In brief, treatments to
advice on general health. A comprehensive neuropsychology test bat- increment activity and reduce sedentary behavior can make use of
tery was used to measure cognition. In sum, the intervention-group modern technology to facilitate activity and to reduce sedentary be-
improved or sustained cognition more than the control group (on the havior and, thereby, reduce the costs of treatment.
test battery, post intervention, the intervention group scored 25% There is strong support for the conclusion that increasing the ac-
higher than controls). The study provides support for the concept that tivity of retirees presenting with minor signs of cognitive decline is
attention to multiple risk factors might be particularly effective in helpful in reducing the likelihood of a rapid progression of cognitive
sustaining cognitive health, even among those at risk for dementia. decline (research cited above and these examples of a larger literature
The selection of risks to treat in the FINGER research is interesting. [70–74]). However, there is no support for increasing the activity of
With the exception of cognitive training, the selected risks are asso- those experiencing dementia will modify major indices of cognition
ciated with a variety of illness and, if moderated for the better would [75]. The implication is clear: Prevention of AD is more likely if begun
improve general health. Generally, better overall health is apt to be a before marked cognitive decline.
condition for better health of the brain, hence sustaining youthful
cognition. Given the relatively small effect sizes associated with the 4.2. Some diets increase the risk of developing AD whereas others seem to
major outcome (differences in cognition) [52] and given that it is un- reduce the risk
likely that the treatment of any one of the risks would counter the
beneficial effects of the other, there are some implications to be drawn As mentioned [74,75], overweight and obesity, having a high serum
from the FINGER research. A reasonable conclusion is that treating cholesterol level [36], and high systolic blood pressure are risks for AD.
other known correlates of developing AD might improve the outcome of Obviously, these factors, each and all, are related to regular patterns of
the combined treatments. Further, if a known risk factor is found to be eating. Eating diets with low levels of salt, sugar, LDL fatty acids and
more salient to AD, then, of course, that risk factor should be treated, if high levels of fruits, nuts, vegetables and HDL is the preferred habit
possible, with the hope of halting cognitive decline. Before discussing because those patterns of eating reduce the risk of obesity and vascular
ways of improving the FINGER research, there is a review and com- ill-health [76–78].
mentary on the treatments used in the FINGER research. There are two longitudinal studies conducted among the partici-
pants of the Rush Memory and Aging Project (Rush U. Med. Center) that
4.1. Inactivity is a correlate of developing AD, and regular exercise reduces assessed the effects of diets on cognitive decline with aging [79] and
the overall risk incidence of AD [80]. With reference to the available research, the
authors selected food-groups they discerned to be helpful in sustaining
It has been posited [53,54] that inactivity is a transdiagnostic the health of the brain during aging while excluding food-groups
condition of ill health. That proposition is similar to Selye’s theory [55] thought not to be healthy (the MIND diet). They developed scores in-
that stress is a common factor associated with many different kinds of ill dicative of the prevalence of using the MIND diet (the MIND diet score).
health, sufficient to be a disease in and of itself. Brain-scans indicate The 10 brain-healthy food-groups were green leafy vegetables, other
that lack of activity reduces signs of health in areas know to be salient vegetables, nuts, berries, beans, whole grains, seafood, poultry, olive oil
to AD, for example, the hippocampus [56–58]. A meta-analytic study and a very limited intake of wine. The 5 unhealthy food groups were

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red meats, butter and stick margarine, cheese, pastries and sweets, and intensive therapy focusing of lifestyle changes did manage to get a
fried/fast food. They also had considerable biographical and health reasonable proportion of those receiving treatment to meet the goal of
data of the participants to use as co-variants of the prevalence of kinds weight loss and to sustain a loss for years. The weight loss and other
of diets with respect to cognitive skills. Among the results was the features of the treatments reduced the incidence of advancing diabetes.
finding that participants with higher education, greater cognitive and Of course, the treatment did not succeed for all. However, the degree of
physical activity and more favorable cardiovascular conditions had a success over control conditions (usual advice) and over the prescription
pattern of eating healthier foods than their counterparts. By statistical of metformin (a standard medicine used to reduce blood glucose levels)
manipulations, the authors controlled for these variables, as well as a is encouraging. Interestedly, there was a comprehensive study whose
host of other covariates (including the incidence of ApoE4) in an at- results were reported in 1980 that showed that CBT designed to reduce
tempt to isolate the effects of a pattern of eating the supposedly healthy body weight was successful [90]. In brief, the CBT designed to control
diet in preference to an unhealthy pattern. Their findings: a pattern of the progression of advanced diabetes is reasonably effective, can be
eating the healthier diet tended to sustain cognitive health as one aged implemented without excessive cost and can be improved. Better use of
and reduced the incidence of AD significantly. An implication of this internet capabilities might reduce the cost of therapy, enhancing its
longitudinal study is that a favorable lifestyle, including a pattern of practicality [88,89].
eating what has been posited as healthier foods, will reduce the pre- Diabetes and AD are both slowly developing, chronic diseases with
valence of cognitive decline including that of AD. common risk factors associated with unhealthy lifestyles known to
There is research [81] indicating that retirees who regularly use produce overweight and obesity and accompanied by being sedentary.
alcoholic beverages might suffer thiamine deficiencies thereby risking Treatments instilling a healthier lifestyle for one of these chronic con-
Wernicke’s encephalopathy, which, in turn, is a risk factor for Korsakoff ditions are apt to be of benefit in reducing the progression of both
syndrome. The Wernicke-Korsakoff syndrome is manifest as memory diabetes and AD. CBT specifically designed to modify eating behaviors
loss. Wernicke-Korsakoff syndrome is, in essence, the death of parti- and activity has been shown to be sufficiently effective to be im-
cular neurons, i.e., those of the mammillary bodies. Disease of the plemented widely. We note the obvious: the costs of enhanced pro-
mammillary bodies and fornix (a major link to the hippocampus) have grams designed to prevent the progression to advanced diabetes and AD
been linked to AD [82,83]. Death of neurons in the mammillary bodies will be minimal compared to the cost of treating advanced diabetes and
occurs rapidly with the complete depletion of the thiamine reserve in AD.
the brain. The prevention of Wernicke’s encephalopathy is clearly, ea-
sily treatable; i.e., provide thiamine by healthy eating or supplements. 4.3. Monitoring known risks for vascular disease may reduce the risk of
Before the complete loss of thiamine, there would probably be debris developing AD
needing to be cleared from the area. Sustained regular exercise will
further debris-removal. More difficult to treat is the alcoholism that It is known that variables such as inactivity and unhealthy eating
interferes with thiamine homeostasis; however, there are reasonable habits are associated with vascular diseases such artery and heart dis-
improvements that can be made in the treatment of alcoholism [84]. eases and strokes. Of particular relevance to AD are hypertension (re-
Given the correlation between the variance in the APOE gene and lated to fluid flow) and hyperlipidemia (lack of optimal cholesterol
the prevalence of AD and the relationship of the products of the APOE homeostasis). Both can be treated by attending to lifestyle changes.
gene to homeostasis of cholesterol, there is an interest in variation in However, a common treatment is to prescribe antihypertensive and
diets with respect to lipids. Essential fatty acids are particularly relevant antihyperlipidemic medications. Both kinds have been assessed for
in as much as there is research to indicate that supplements of them their ability to treat signs of AD. The results indicate a mixed picture
prevented indications of AD in mice who had bulbectomies [85] (also [70]. Some studies indicate a benefit to prescribing antihypertensive
see [86] for a relevant, supportive study with elderly citizens). and antihyperlipidemic medications medicines whereas others do not.
Being overweight, obese, pre-diabetic, suffering Type II diabetes For example, there are recent reviews addressing statins for their pu-
and Type II diabetes that evolves into Type I as well as a sedentary tative utility in preventing the progression to advanced AD; one sug-
lifestyle are all correlated with an array of vascular problems including gested a benefit [91], whereas the others did not [92].
small infarcts in the brain. Each item of the list is correlated with the In 2012, the Food & Drug Administration (USA) added a warning to
development of AD [5,87]. Each of these chronic conditions is related to the labels for statins indicating that their use may raise the levels of
what has come to be known as an unhealthy pattern of eating which sugar in the blood and could cause memory loss. Statins’ benefit in
involves excessive (more than “burned”) calories taken nearly every reducing blood cholesterol may be offset by their side-effects. It is not
day by way of considerable intake of palatable food. The palatable food known whether the prescription of antihypertensive and anti-
often contains considerable sugar, fat, and salt without providing a hyperlipidemic medications are the cause of a gradually yearly (from
sufficient variety of foods to provide adequate nutrition. The palatable 1969 to 2014) decrease in deaths due to heart attacks and strokes
food sold in many fast-food restaurants and in packaged-prepared foods (deaths per 100,000 population) or other factors such as the adoption of
contains too much sugar, fat and salt to be healthy (particularly if taken healthier lifestyles. Given that the USA has about 5% of the World’s
frequently). This is common knowledge (e.g., [78]). population, but purchases 50% of the World’s available medicines [93],
Treatment of overweight and obesity (which obviously involves but does not have better signs of good health, does gives rise to the idea
changing eating habits) are notoriously difficult to engage and, if en- that there might be an over-prescription of medicines with side-effects
gaged, to sustain. The crux of the issue involves behaviors (eating and that outweigh possible therapeutic effects.
physical exercise) and, therefore, should be amenable to behavioral
interventions. There are tests of the potential for behavioral therapy to 4.4. Specific cognitive training may reduce the risk of AD
be effective within the context of treatment of diabetes.
Weight-loss of somewhat greater than 7% of body-weight when Individuals with more advanced levels of education and who reg-
evidencing Type II diabetes (or predictive signs of getting Type II) has ularly deal with complex intellectual challenges, probably involving
been shown to be helpful in reducing blood glucose and relevant hor- extensive use of working memory, are at less risk of AD [50,60–63,94].
monal levels (indices of eventual serious disease). There have been two The converse is equally true; those with little formal education and who
large-scale trials featuring behavioral interventions designed to effect do not regularly engage intellectual challenges are at a higher risk. The
weight loss. Each trial was discussed recently [88,89] (as part of an question arises: Can we arrange educational opportunities at retirement
entire issue of the American Psychologist) on psychological contributions ages that will do the same as having advanced levels of education that
to control of diabetes. The conclusions drawn indicate that rather encourage intellectual challenges and, thereby, reduce the risk of AD?

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The available research surely indicates that many interventions with demonstrated that computer-assisted game-like training focusing on
the goal of enhancing cognition, and in particular memory, are not very enhancing visual processing speed and spatial abilities (in particular,
effective in producing lasting enhancement of cognitive ability. For training for enhanced peripheral vision) can change older participants’
example, encouraging working at crossword puzzles, attempts to learn capabilities sufficiently to reliably reduce the incidence of motor ve-
a second language, enhanced time spent reading and similar activities hicle crashes [107]. Thus, there is a precedent for incorporating game-
are not easy to instill among those who do not ordinarily engage such. based training for sensory processing to enhance other behaviors re-
Further, when there is some progress at getting individuals to engage lated to safety and well-being of aged individuals.
these kinds of activities more than usual, there is no evidence that it Based on these early demonstrations that computer-assisted game-
modified ability to deal with other cognitive challenges [17,95–99]. like programs could enhance cognition among some persons and stoked
That is, people may become somewhat more proficient at crossword by individuals’ desires to improve their cognitive abilities, considerable
puzzles, but still routinely forget where they left the car-keys. One can commerce has developed selling programs advertised to improve such
encourage a strategy that is beneficial such as always putting the keys fundamental cognitive abilities as memory and attention. Some of these
in the same place. However, practicing that strategy does not help re- commercial programs are surely more sophisticated than others. If one
solve other cognitive challenges such as remembering to buy needed takes as an index which of these programs is mostly based in the re-
toilet paper. levant science (e.g., numbers of germane published peer-reviewed ar-
There is an approach, derived from the concepts of brain plasticity, ticles and Federal grants awarded), then the scientists who developed
that appears to have promise for enhancing global cognition. The basic the programs of Posit Science are surely the leaders in developing sci-
idea is that the brain is continually being organized by perceptual input ence-based programs with the possibility of actually improving memory
and that certain daily activities actually trains for less efficient cogni- and attention. The current programs offered by Posit Science are very
tion because it limits perceptual capabilities. For examples, we walk on sophisticated, designed to sustain practice and available at reasonable
smooth surfaces and lose skill at walking on rough, bumpy, uneven cost. Further, they allow the collection of data on the amount of use and
terrain. We spend hours looking straight ahead while watching televi- progress with practice.
sion and driving a car and our brain responds by facilitating such The advantage of practicing memory and attention might not be
viewing at the expense of peripheral vision [100,101]. enhancing the ability to memorize and to attend directly, but rather the
The advent of the technology that allows for video games provides enhanced fluid flow that might be engendered by practice in networks
technology for a new approach with the goal of modifying established involved in memory and attention. In other words, sustained cognitive
auditory and visual perceptual processes that are not utilitarian to activity likely induced enhanced fluid flow that may clear an accumu-
perceptual processes that are more utilitarian. This technology has been lation of excess Ab in anatomical areas that are previously only peri-
used to develop computer-assisted game-like programs with the express odically, but not regularly, active.
purpose of enhancing cognition. A germane question: Can these com- Consideration of the extensive research associated with treating the
puter-assisted game-like programs induce sufficient activity in relevant risks for AD that were treated in the FINGER research and the rather
neural networks to strengthen overall cognitive ability? Further, if such impressive research supporting the idea that treating those risks is
programs can strengthen cognition, will such reduce the risk of AD? likely to reduce the prevalence of AD, it seems that widespread im-
One relevant example is associated with Prof. Merzenich and his plementation of treating those risks is a treatment of choice for a con-
colleagues, including a former student of his (Henry Mahnche) [11]. dition that appears to be incurable and not preventable. Further, we
They formed a company, Posit Science, to market programs designed to posit that a program of treating risks for AD can be improved by at-
enhance “brain fitness. Early in the history of Posit Science, a com- tending to other risks, namely treating loss of olfaction and difficulty
prehensive, well-controlled, randomized study was conducted with the sleeping. Loss of olfactory ability (hyposmia and anosmia) is an early
express purpose of testing the idea that a computer-assisted game-like sign of impending AD (e.g., [108–114]) and disturbance of sleep is also
program that was designed with ideas of brain plasticity in mind would a known risk for developing AD [115,116].
enhance memory [102]. The study is a model of a scientific test of a
complex proposition. For example, the statistical analyses of the results 5. AD and the olfactory brain
were done by an independent group. In brief, the trial involved citizens
aged 60–87. There were 3 groups, a group that received the training Much of the content of this section follows from an article by Prof.
designed to improve cognition based on brain plasticity rationale Ethell [21] and describes ideas about the role of fluid flow and olfaction
(sustained practice at enhancing visual and auditory perception), an for AD. In accordance with the amyloid theory of AD [1], Ethell posits
active control group, and a no treatment group that was merely tested that the essence of AD is an inability of CSF-flow to regularly clear
for memory at the same time the other groups were tested. Care was metabolic products, particularly excess Ab, from the interstitial fluid of
taken so that the active control group engaged activities that might the brain [21]. More specifically, Ethell posits that disease at the brain-
enhance memory and cognition, e.g., watching educational lectures and nasal cavity (B-NC) interconnection interferes with the steady removal
taking tests on their contents. The active control group engaged the of excess Ab. It was estimated that over 80% of the bulk flow exiting the
same duration of activity as the group with the experimental treatment, cranium is by way of the functionalities of the B-NC interface [117];
i.e., 60 min a day, 5 days a week for 8–10 weeks. In brief, the experi- however, new theories may challenge that value, which will be dis-
mental treatment group demonstrated improved performance on tasks cussed. There are reasons to focus attention on the B-NC interface, one
of memory that were different from those used in training whereas the of which is that it is vulnerable to disease.
two control groups did not. The difference in outcomes was indexed by
an effect size of 0.25. The implication is that the approach developed by 5.1. The tissues of the nasal cavity are vulnerable
Merzenich and colleagues is different than what was attempted before
in trying to improve cognition among the elderly; different in concept The dendrites and cell bodies of the olfactory nerves are actually
and different in effectiveness. Now 10 years after this demonstration outside of the cranium, embedded in the olfactory epithelium of the
and based on continuing research, many conclude that specially-designed nasal mucosa. Olfactory nerves (axons) extend through the cranium by
computer-assisted game-like programs are useful and it would benefit way of the numerous foramina of the cribriform plate of the ethmoid
healthy aging if widely used [8,10,100,101,103–107]. bone, which separates the nasal cavity from the meninges, with their
Prior to the work described above, there is the research of Prof. Ball CSF-filled subarachnoid space, and the olfactory bulb. At the nasal
of the University of Alabama at Birmingham. She and her colleagues, epithelium, flowing CSF merges into lymph vessels that are part of
across the years and with multiple studies [100,101], have cervical lymphatics [21,118]. Any event disrupting the functionality of

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fluids exiting the cranium via the cribriform plate, as well as disrupting AD to those without AD [20]. Those with AD had extensive neurofi-
the olfactory nerves and their supporting tissues at the cribriform plate, brillary tangles and reduced cell density in the anterior olfactory nu-
would have unhealthy consequences. Those unhealthy consequences cleus; and, those without AD had not suffered such. The distal portions
include less efficient bulk flow from the brain to the cervical lymphatics of the olfactory system are clearly affected in those manifesting AD
and hyposmia and anosmia. [20]. AD is characterized by a progression of ill health from the ol-
Because the tissues of the nasal cavity are exposed to the air of factory bulb, anterior olfactory nucleus to other segments of the limbic
breathing and sniffing, they are subject to a variety of adversities. The brain (importantly to the hippocampus thereby affecting memory) and
most common of which are infections due to growth of virus, bacteria, eventually to nearly the whole brain [21,128–131]. There is an ex-
fungi, protozoa and perhaps an accumulation of allergenic particles and tensive review [132] detailing the information supporting the idea that
immune processes which attempt to combat infections or allergens. onset of <AD is likely to begin at the distal portions of the olfactory
Poisonous fumes can also severely damage the functionalities of fluid brain and then spread to the more central portions of the olfactory brain
flow and olfaction. Even the intense air pollution of some urban centers and then to nearly all of brain (also see [131]). Also, it is noted that
might be toxic [119,120]. Some commonly prescribed drugs may also olfactory bulbectomy in mice leads to accumulation of metabolic and
affect olfaction [7,121]. Ethell pointed out that physical trauma to the cellular debris in the entorhinal cortex [133], a cortical area for ol-
head can disrupt the fragile structures of the cribriform plate hence factory perception and involvement in hippocampal functioning.
disrupting fluid flow [21]. Physical trauma can also move the brain and A recent article addressed the issue of whether AD starts in the basal
olfactory nerves against the more stable skull shearing the olfactory forebrain or in the entorhinal cortex by measuring shrinkage in gray
nerves traversing the skull. Ethell posited a potential causal link be- matter volume of the basal forebrain and the entorhinal cortex [134].
tween such physical damage and AD because the trauma would disrupt The issue was addressed by measuring the relative size of the two areas
fluid flow regulating the concentration of Ab [21]. from those suffering various stages of AD during autopsy. The conclu-
The loss of olfactory perception is an early sign of impending, fully sion was drawn that the basal forebrain suffered somewhat earlier da-
developed AD (e.g. [20,48,79,108–114]). Loss of olfactory perception mage than the entorhinal cortex. Using advanced technology to esti-
has multiple consequences. Most individuals are disturbed by hyposmia mate the number of neurons in an area of autopsied brains, an earlier
and anosmia. Hyposmia and anosmia also reduce the pleasures of taste, study addressed the loss of tissue in selected areas of the brain with the
thereby, contributing to the anhedonia characteristic of clinical and advancing signs of AD (from no signs of AD to dementia) in each of
subclinical depression. It is notable that changes in mood/depression three areas of the human brain: (a) nucleus basalis of Meynert, (b) locus
may be a very early sign of AD [122]. Also, olfactory bulbectomy is an coeruleus, and (c) entorhinal cortex [135]. For example, the neuron
animal-model of depression [123]. And, it has even been posited that number of a heathy 80-year-old for nucleus basalis of Meynert is esti-
olfactory bulbectomies might be an animal-model of AD because the mated to be 167,200 to 215,827; there is a small loss in neurons among
consequences of bulbectomies resemble those of AD [124]. As well, those with earliest signs of cognitive decline and extensive loss among
animal models of AD show both cognitive and affective dysfunction those with advanced AD (83% loss) [135]. There was progressive loss of
[42,43]. neurons in each area sampled as AD advanced. The nucleus basalis of
Authors often conclude that neuro-degenerative diseases cause loss Meynert is a source of cholinergic innervation of the olfactory bulb. The
of olfactory perception. For example, Mackay-Sim and colleagues have locus coeruleus is a source of noradrenergic innervation of the olfactory
described how “…many neurodegenerative diseases also induce loss of bulb [136,137]. The entorhinal cortex is a place receiving innervation
olfactory function.” ([7], p. 763). However, it is equally plausible that a from the olfactory bulb as well as cholinergic innervation [138]. With
feature of olfactory dysfunction may induce neurodegeneration, a the focus on determining which of these central areas of the brain has
proposition finding support in a report showing anosmia is correlated to the earliest and most severe loss of tissue, the focus overlooked the
a loss of cortical gray matter [125,126]. possibility that the initial disease was likely at the B-NC interface. The
Mackay-Sim et al. [7] related results from a survey of adults of various idea is that induced disease of the olfactory bulb (vulnerable to disease
ages and confirmed that the quality of olfactory perception tends to de- at the B-NC interface), in turn, induces disease in areas providing both
crease with age. However, a different perspective emerged when the tested cholinergic and noradrenergic input to the bulb, i.e., the nucleus basalis
participants were separated into two groups: one was characterized as of Meynert and locus coeruleus. Such tissue loss eventually proceeds to
having a history of nasal problems and taking a variety of medications, entorhinal cortex, the hippocampus and large segments of the cortex. It
and the other group was characterized has having no history of nasal follows that any effect that might prevent or halt disease at the B-NC
problems and not taking a variety of medications. The medications in- interface might also halt the progression of AD.
cluded those routinely prescribed to an elderly population, i.e., anti- We have information indicating that a major source of bulk flow
hypertensive and antihyperlipidemic medications that had been shown to from the brain to lymphatic system is at the brain-nasal cavity (B-NC)
be associated with reduced olfactory ability [121]. Those with known interface. We have noted that the distal portions of the olfactory brain
nasal problems and/or taking a variety of medications did show a marked are susceptible to a variety of illnesses. In addition, loss of olfactory
decline in olfaction as a function of aging. The trouble-free group, with a perception is an early risk factor for the development of AD. And, there
small incidence of prescribed medications, did not show a marked reduc- is a progression in the development of AD that begins with the loss of
tion in olfactory perception as a function of age. Evidently, among the neural tissue in the distal portions of the olfactory brain and progresses
generally healthy elderly, the processes of neurogenesis known to occur in to the more central portions of the olfactory brain. An issue emerges:
the olfactory epithelium was sustained sufficiently to maintain olfactory How could disease at the B-NC begin a progression of disease that
perception [127]. The conclusion: Degradation of olfactory perception is would eventually destroy nearly all of the hippocampus and wide
not an inevitable consequence of aging. portions of the cerebral cortex. The next section addresses that issue.
In addition to noting that loss of olfaction is a correlate of devel-
oping AD and noting that the olfactory anatomy is susceptible to dis- 5.3. Disease at the B-NC interface is apt to reduce fluid flow through the
ease, there is research supporting the idea that the distal portions of the distal portions of the olfactory brain, hence lead to excess Ab with interesting
olfactory brain are the sites where the development of AD begins. consequences

5.2. Perhaps, AD begins in the distal portions of the olfactory brain Neuro-vascular and neuro-metabolic coupling is a name given to the
relationship between local neural activity and changes in the vascular
Interesting differences were found in the first post-mortem study to and metabolic processes that provides the nourishment needed by
directly compare the histology of the olfactory bulbs of patients with heightened neural activity [87,138–140]. In brief, it is posited, that

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neural activation triggers vasodilation hence increases blood flow to an larger percent than those who did not practice [149]. Recently the
active area; and concordantly, and of necessity, less blood flow to areas training regimen has been modified [148]. After many days sniffing the
of less activity (a functionality making functional magnetic resonance initial four scents twice daily, the participants were presented four new
imaging, fMRIs, possible). Any area of the brain not activated beyond a scents to sniff daily, again, for many days. This rather small change in
basal state of readiness must nevertheless sustain energy-use to main- the daily regimen led to 63% measurable improvements in olfaction
tain membrane potentials; hence produce metabolic products, including [148]. Further, there was an indication that those who engaged olfac-
Ab. If disease at the nasal epithelium has blocked olfactory stimulation tory training within a year of loss of olfaction were more likely to re-
by the olfactory nerve, then that malfunction would drastically reduce cover olfactory perception [148,149]. Together, these studies demon-
stimulation of the olfactory bulb. Consequently, the bulb would not be strate the possibility of olfactory training to reduce olfactory
an area of high activity and be an area of reduced fluid flow and be dysfunction; albeit, there may be windows of sensitivity after the dys-
subject to an accumulation of metabolic products that might have toxic function manifests.
effects. Further, the invasion of infectious agents along perineural At issue: How does merely sniffing daily among those with anosmia
pathways might cause death of neurons in the olfactory bulb and in- engender the plasticity necessary for recovery of lost olfaction? Some
flammation. recent findings are germane. Sniffing among those with anosmia en-
A chronically quiescent olfactory bulb (e.g., due to reduced olfac- hances activity in olfactory cortical areas [155] as well as other areas of
tory sensation and a consequence of a variety of diseases at the B-NC the brain [158] that might be critical to olfaction. For example, sniffing
interface) might lead to an accumulation of metabolic waste that may is critical to the perception of the source of a scent and for sensing the
lead to events that are not healthy first for the anterior olfactory nu- potential toxicity of the source of scents. In brief, sniffing is an integral
cleus, and then progressively not healthy for the lateral olfactory tract, component of olfactory perception [159]. The basis of fMRIs to index
and its connections [132]. If there is cell death, there are likely to be neural activity is that neural activity induces fluid flow and associated
immune processes (probably involving Ab [141] and, of course, mi- oxygenated blood, which can be indexed by MRI. Consequently, when
croglia) that can be overwhelmed by the extent of the damage and there is recovery of lost olfactory perception, it is surmised that there is
hence contribute to further ill health by forming even larger clumps of increased neural activity, hence increased vascular activity within the
“trash” needing to removed [142]. Also, if fluid flow at the cribriform olfactory brain. Actually, it is difficult to imagine how it would be
plate is totally blocked, then there would be considerably reduced otherwise, neural activity demands constant nourishment and removal
means of removing the accumulated debris from the area. This line of of metabolic products from interstitial fluids surrounding neurons.
thinking supports Ethell’s hypothesis that disease at the B-NC interface Sniffing, therefore, might enhance the relevant flow of CSF and, per-
can be an initiating event in the development of AD [21,132]. There is haps, neuropoiesis in portions of the olfactory brain.
also an implication that can be drawn from this line of thinking. Any
activity that would restore any reduced levels of fluid flow to the distal 5.6. Some caveats
portions of the olfactory brain is likely to be therapeutic.
The hypothesis that the B-NC is the place where CSF interacts with
5.4. Treating lost olfactory perception may halt the progression of disease in the lymphatic systems is incomplete. It does not account for the fact
the limbic system that eventuates into full-blown AD that the blockade of the flow through the cribriform plate does not
immediately lead to rather disastrous effects. Consequently, there must
There have been extensive reviews on the topic of addressing po- be alternatives for metabolic products generated in the brain to get to
tentially preventable risks for developing AD (e.g., [60–63]). Notably, the lymphatic system other than at the B-NC interface. Recent dis-
none have addressed the possibility that treating hyposmia and anosmia coveries [160,161] have confirmed [162] that there are functional
might be a way of reducing the risk for AD. Perhaps, that is the case lymph vessels lining sinuses of the dura mater thereby providing a
because until recently there was not sufficient recognition that mal- connection between the CSF of the subarachnoid space to the cervical
functions at B-NC interface might be causally related to AD (however, lymph system. In mice, lymph vessels were associated with cranial
see [21,132]). Also, until recently there were only a few studies in- nerves (particularly cranial nerves II, V, IX, X and XI) as they exited the
dicating that hyposmia and anosmia were easily treatable. Physical brain. Lymph vessels are also observed in the dura lining the cribriform
blockage of the nasal passages (e.g., by tumors or infections) are often plate [160]. Lymph vessels were also associated with the middle cere-
treatable, but the long-lasting effects of the disease at the B-NC interface bral artery, an artery serving the dura mater. If the exit of fluids at the
may lead to chronic loss of olfaction. Until recently, there were no cribriform plate was blocked, the additional connections between CSF
known cures for chronic anosmia or hyposmia due, for example, to and the lymphatic system associated with the dura mater could account
lingering effects of infections. for a means of regularly moving excess Ab from the subarachnoid space
Anosmia and hyposmia are associated with a number of problems, to the cervical lymphatics. Nevertheless, the reduction of flow from
e.g., reduced ability to sense spoiled foods and smoke. The loss of brain to the lymphatic system due to disease at the B-NC interface
pleasures from eating seem to be particularly problematic for the el- might result in a slow accumulation of Ab in the distal olfactory brain,
derly [143]. Also, loss of olfactory perception is associated with clinical and a slow accumulation of Ab is a hallmark of the beginnings of AD.
depression [144], which in turn is a risk factor for AD [145–147]. Positing that disease at the B-NC interface disrupts fluid flow which
Consequently, the successful treatment of hyposmia and anosmia would ordinarily removes excess Ab by itself does not specify how excess Ab
be beneficial regardless of its potential benefits in halting the progres- leads to death of neurons and glia. Given the susceptibility of neurons to
sion of AD. disruption of blood flow at the capillary beds, it is likely that excess Ab,
Ab-plaques and an inducement of immune processes somehow, to-
5.5. New procedures have been developed that effectively treat hyposmia gether, block the regular flow of blood through the capillary beds
and anosmia [6,87], hence starving neurons to death. Treating multiple risk factors
associated with AD, including hyposmia and anosmia, are likely to
Across the last few years, a few studies have demonstrated that daily sustain healthy bulk flow of fluids throughout the brain.
training with scents has improved olfaction [148–159]. The regimen Positing that interference with circulation of blood to distal portions
used is remarkably simple. The participants have merely been directed of the olfactory brain does not, by itself, explain how the damage to the
to every morning and evening, to sniff, for 10 s or so, each of four distal portions of the olfactory brain slowly, but insidiously, causes cell
scents. By doing so for months, about 30% of those presenting with death in adjacent tissue. It is posited that cell-death at a focal area in-
hyposmia or anosmia recovered some of their lost olfaction; a much cites cell-death in adjacent areas. Cell-death spreads from one damaged

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area to the next and so on until there is dementia. The critical event We note that the procedures used by Nedergaard and colleagues
may be the accumulation of proteins that are not cleared sufficiently. [22,168–170] did not allow for measures associated with a full cycle of
There is recent research indicating that excess Ab might be toxic itself. healthy sleep, i.e., a periodic shift from non-REM sleep to REM sleep
He et al. injected human Ab1-42 into the mouse olfactory bulb and then that characterizes healthy sleep. Consequently, the shifting levels of
tracked the spread of the injected material [163]. They found that the brain activity (measured by EEG activity) from non-REM sleep to REM
injected Ab spread to areas adjacent to the injected area and induced sleep (paradoxically awake-like brain activity while asleep involving
neuronal apoptosis in the adjacent areas. They concluded that Ab dreaming) was not considered in their formulations. Extending our
peptides could readily move via neural connections and that excess Ab extrapolations from (a) understanding of the essentiality of neuro-vas-
is toxic. cular coupling, (b) the requirement that all areas of the brain cannot
simultaneously have high levels of vascular input, and (c) that efficient
5.7. Summary on the olfactory brain and AD waste management of the brain demands that all areas of the brain have
substantial activity periodically, but regularly, thereby having sub-
Treating lost olfactory perception and strengthening ordinary ol- stantial fluid flow, it is speculated that: as Nedergaard and colleagues
faction might further reduce the risks of AD when engaged along with posit [22,168–170], during sleep there might be systematic changes in
the risks treated in the FINGER study. Further, the treatment of olfac- fluid flow that might contribute to better “waste” management. Also
tory deficits is easy to implement; and evidently readily engaged. potentially relevant, there is more production of CSF during sleep-time
Further, the recognition that olfactory training might reduce the risk of [23]. We posit that the shifting levels of activity among brain areas
AD is apt to sustain olfactory training. With the goal of preventing AD, during sleep (cycles of REM and non-REM sleep) might be a mechanism
it seems rational to add testing for olfactory deficits. If olfactory deficits for areas that might not have been particularly active while awake to be
should be present (and not due to features such as physical blockage of active during a period of sleep. It might be therapeutic with respect to
the nasal passages), then it just seems reasonable to engage the simple AD to attend to the risk of sleep disturbances.
treatment of briefly, but regularly, practicing sniffing and attempting to
smell a variety of scents for many days. Further, it appears to be best to 6.2. Treatment of sleep disorders will improve CSF flow, hence treat AD
engage the treatments of practicing sniffing as soon as a deficit in ol-
faction is recognized. Daily exercise is apt to further the effects of ol- There are recent reviews [164,175] on sleep and AD. Sleep dis-
factory training because both would induce more fluid flow at the B-NC ruption is a prodromal sign of AD [115,116,163]. Also, the con-
interface leading to less accumulation of Ab, hence no excess of Ab. sequences of sleep disruption might contribute to the progression of AD.
We believe that behavioral treatment for hyposmia and anosmia has As symptoms of AD progresses in severity, so does severity of sleep
yet to be tried as a part of a comprehensive program designed to pre- disruption. The sleep disturbances common to AD include increased
vent AD. There is another risk factor that also seems particularly salient sleep in daytime, increase frequency of nocturnal awakenings and a net
to the development of AD that has not been a part of a program to decrease in both slow wave and REM sleep. Also, confusion and agi-
prevent AD; i.e., treating the risk factor of disturbed sleep. Along with tation are worse later in the day among those with clear signs of AD.
hyposmia, disturbances of healthy sleep are signs of imminent AD There is a possibility that commonly prescribed hypnotics may con-
[116,164–167]. tribute to sleep problems (and their correlates) rather than treating
them, except in the very short-term (most widely used hypnotics in-
6. Recent studies of sleep add to the theory on ordinary, regular terfere with REM sleep and memory consolidation).
fluid flow in the brain Fortunately, there are effective treatments for common problems of
sleep. Extensive, well-done research indicates that CBT for insomnia
Prof. Nedergaard and colleagues [22,168–170] and others (CBT-I) was and is likely to be effective [176]. Studies of comparative
[171,172] studying the brain during the circadian cycle have made effectiveness confirm that sleep problems should be attended to by CBT-
observations germane to the maintenance of homeostasis of the brain’s I rather than by hypnotics [176–178]. These studies led American
fluids. Total volume of fluids in the healthy brain remains nearly con- College of Physicians to recommend CBT-I in their new clinical practice
stant, but the proportion of fluid might vary among the various fluid guide for management of chronic insomnia [177,179]. Pharmacological
compartments of the brain, i.e., varies among the ventricles and sub- treatments for insomnia can be effective, but risk adverse side-effects
arachnoid spaces, the extracellular space, the intracellular space and which are problematic for people at risk for AD, e.g., memory-problems
the fluids associated with arteries and veins. Interestingly, it is posited [180]. If drugs are used to treat insomnia, they should be used under
[170] that the fraction of extracellular volume is about 14% during the the general rubric of “psychopharmacology is merely a setting condi-
awake state compared to about 23% during the sleep state (data from tion for psychotherapy.”
mice), i.e., about 60% from awake to sleep. It is posited that the greater There is counseling usually embodied with CBT-I called sleep hy-
volume of extracellular fluid during sleep facilitates the removal of giene. Sleep hygiene is rather common sense advice on how to treat
metabolic products, notably accumulation of Ab. Such a proposition is insomnia. Often sleep hygiene is the provision of a checklist of activities
supported by data indicating that Ab is probably cleared twice as fast that a patient might engage, including such things as do not drink coffee
during sleep compared to being awake [170]. Interestingly, a single close to bedtime and establish a regular time to go to bed and when to
night of sleep deprivation led to elevated levels of Ab-42 in healthy get out of bed. Those who comply with the advice often have a better
middle-aged men [173]. quality of sleep. Further, sleep-hygiene-advice can be effectively de-
livered over the internet, hence be cost-effective [181]. A treatment
6.1. Some caveats program designed to treat the first signs of AD [175] would attend to
sleep problems beginning with sleep-hygiene-advice; and if that does
There have been serious questions (e.g., [23,174]) raised con- not succeed, a referral to someone who can deliver more comprehen-
cerning the generalization that there are marked changes in extra- sive CBT-I.
cellular volume as a function of being asleep or being awake. The
questions revolve around the idea that the observations may be peculiar 7. Treating multiple risk factors might be particularly effective in
to the preparation used to measure changes (e.g., using barbiturate sustaining cognitive health
anesthesia); and the impossibility that such volume changes might not
occur ordinarily because it would involve nearly pathological changes Imagine a brain fitness center associated with places where elders
in osmotic balances between fluid compartments [174]. congregate such as retirement communities, assisted living facilities,

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and senior citizen centers. Also, there could be places specifically es- “work” necessary to effect plasticity. Also, treating the risk factors of
tablished to engage retirees in activities that will reduce the risk of AD. lost olfaction and disturbed sleep involve little time-consuming “work”
There may be opportunities to cooperate with those working to prevent (but sustained attention) and when successful have enduring effects
diabetes. Such centers would collect information germane to testing the that will be sustained without further attention to the problems. The
general concept that treating multiple risk factors for AD would delay idea is that it is surely possible to improve on treating known risk
the onset of AD. factors and provide a potentially larger benefit than what was de-
The centers would be places for obtaining baseline data, such as monstrated in the FINGER research [51] and further the improvements
results of tests of cognitive ability and information on general health. can be made in a cost-effective way.
There would be testing for hyposmia and anosmia and cognitive abil-
ities, thereby, having the means of advising participants to engage a 7.1. Some caveats
regimen of brain fitness designed to prevent AD. Many with reduced
olfactory perception and mild cognitive decline may not be particularly The belief that one feature of a healthy lifestyle is sufficient may be
aware of the extent of their losses or more likely attribute them to the a limited perspective. Attention to inactivity by prescribing exercise has
inevitability of aging. Making elders aware (a) of their potential losses been shown to be helpful in preventing cognitive decline and hence
(b) the good possibility that relevant practices might restore losses, and may be helpful in preventing AD. However, it is unlikely that a program
(c) that restoration to a normal level of functioning might delay onset or of exercise by itself will prevent the high prevalence of AD among re-
even prevent AD may persuade elders to commit to engaging in activ- tirees. Studies addressing this issue show that the variable of exercise
ities to prevent AD. accounts for only a percent of the variance in measures indexing pro-
The beneficial results of the FINGER study [51] encourage attempts gression toward AD. We are focused on treating lost olfaction as being
to improve on treatments they designed to halt the development of AD. an important feature of a program designed to prevent AD. It is likely
For example, making use of modern technology (e.g., exergaming that treating lost olfaction may be helpful in preventing advancement of
programs and using best learning theory practices that would more AD, but may not be sufficient by itself to end the high prevalence of
fully reward the relevant activity). Also, we posit that there can be developing AD among retirees. We posit that CBT for AD which ad-
substantial improvements in the treatment by adding to the risks that dresses multiple risk factors associated with the development of AD will
they treated. In addition to treatments used in the FINGER study, have a much better chance of markedly reducing the prevalence of AD
considerable attention might be directed toward treating hyposmia and then alternatives that address only one aspect of the problem.
anosmia. There would be available treatments for sleep disorders.
There would be stations with computers for the systematic collection of 8. Differing perspectives
data as well as a place to introduce and encourage practicing cognitive tasks
designed to strengthen cognition such as those commercially- available There is the question of whether Ab is similar to carbon dioxide, i.e.,
[11,164]. Even ordinary daily computer use has been proposed to facilitate metabolic “waste” with little if any utility and needs to be removed; or
cognitive functioning and enhancing hippocampal volume in older in- similar to glutamate, a necessary product whose accumulation beyond
dividuals [182]. That center might be equipped with a few modern, its utility is problematic. There is support for the concept that Ab is
treadmills or stationary bikes to encourage physical exercise (i.e., ex- more similar to glutamate. The genes producing Ab are phylogeneti-
ergaming) [68,69,75,155,158,159,175,176,183–185], thereby, improving cally conserved [187], Ab is nearly constantly produced [188], and Ab
CSF flow [21]. For those who can afford computers and exercise equipment has functionalities [141,189]. More telling, however, is the fact that
at home, there will be encouragement to engage cognitive training as well putative therapies based on the notion that Ab is garbage, waste, debris
as exercise at home. or like a microbe have failed to prevent the cognitive decline char-
The centers would be a place for giving advice on sleep hygiene. As acteristic of AD (e.g., [190–194]).
indicated above, CBT-I might be indicated for those for whom advice on Notice the difference between what is current (find the elusive
sleep hygiene was not helpful. Also, new research has indicated that medicine) compared to what is proposed. The extant perspective tends
skillful adjustment of the lighting of the places where retirees live almost to ask retirees to be passive and to hope that the experts on
would nudge toward healthier sleep [186], which, in turn, is germane molecular biology will find a cure for AD, just in case they are among
to the prevention and treatment of AD. the unlucky ones who will “catch” AD. What is really quite different is
It seems obvious that better nutrition, better sleep, better exercise, that CBT for AD asks retirees to be active participants in sustaining their
and cognitive engagement will reduce the risk of diseases of the brain; brain-health. CBT-AD prescribes activities which in turn have a chance
nevertheless, little is done to encourage and sustain healthy lifestyles of sustaining the molecular biology of the brain typical of their younger,
among those at retirement-age and particularly those who might need healthier, productive years. Also, the prescription of the activities of
special support for engaging health-sustaining activities (e.g., very CBT-AD has a reasonable chance of halting the early stages of devel-
gradual introduction to an exercise program or attention to lost olfac- oping AD. The beneficial changes in the brain can come about by way of
tion). We promote the idea that treatment of hyposmia and anosmia persistent activities because persistent activities engage the complex
should be routine, rather than ignored. Even marginal enhancement of physiology of the brain (e.g., modifying fluid flow) consequently more
treatment of problems of olfaction and sleep will reduce the risk of likely to make system-wide changes (e.g., within the olfactory brain).
lethargy and depression which, in turn, will facilitate general activity The brain of a sedentary, intellectually inactive individual who has
and, thereby, reduce the risk of AD. sleep problems is organized by those activities, and that organization
The earlier prognostic signs of advancing AD including lost olfac- has unhealthy consequences (e.g., an accumulation of Ab, leading to
tion, sleep disturbance, chronic inactivity, and mild cognitive decline excess Ab, and toxicity). We posit, following others, that consistent
need not be merely signs of unremitting accumulation of Ab plaques, physical exercise, specific kinds of cognitive exercise, activity toward
but rather conditions that can be remedied. If these prognostic signs are healthy olfaction and efficient sleep will also organize the brain, but for
remedied, they will most likely prevent what has seemed to be the in- the better (with reference to AD, no or limited excess Ab throughout the
evitable slow erosion of the brain that is AD. Treating selected risk olfactory brain).
factors will very likely sustain the ordinary, regular healthy removal of Prescribing drugs or vaccinations are not likely to correct a seden-
excess Ab as occurs during pre-retirement years and in about half of tary lifestyle and induce a more active lifestyle with cognitive chal-
those reaching the age of 85 years. lenges (e.g., such as learning to dance and then regularly dancing often
The technologies of modern video games can be applied to make and getting better at it [195]). We can, however, prescribe activities
cognitive training and exercise more rewarding, hence reducing the that support healthy fluid flow in the brain and skillfully nudge retirees

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to engage activities that replace unhealthy patterns of behavior. This cognition are indications that fluid flow throughout the brain, and
generalization does not obviate the possibility that a drug or a nutri- particularly at the B-NC interface, is sluggish [21]. Therefore, fluid flow
tional intervention might not be useful in helping retirees to actively at the B-NC interface probably needs rehabilitation. Further, we posit
sustain the health of their brains. that each of the listed symptoms can be rectified by engaging some
Note that the combination of successively treating hyposmia and time-consuming, but rather simple, activities. Cognitive behavioral
anosmia (practice at sniffing), improving patterns of sleep (CBT-I), in- treatment for AD would involve the following: training for better ol-
ducing a healthy level of daily activity (try exergaming), encouraging faction, engaging the already well-developed CBT-I, engaging the al-
healthy eating habits (e.g., the MIND plan), and practice at tasks in- ready well-developed computer-assisted game-like programs to sustain
volving working memory and attention (selected computer-assisted cognitive skills, using exergaming to enhance activity which, in turn
game-like programs), might each and all, facilitate clearing the brain of will stimulate CSF flow throughout the brain. Also, providing advice on
excess proteins. Further, treatments for these lifestyle variables are well nutrition and drug-use is apt to be helpful. Further, much of this
within our technology to do so beneficially and to do so in a cost-ef- therapy can be engaged by the elderly without much professional help
fective manner. (much of it is already automated). Even further, the advocacy of these
Modern research has discovered there are potentially multiple ways practices is supported by considerable research that supports the idea
for clearing the brain of excess Ab (and potentially other proteins) in- that early stages of AD are fundamentally a failure to sustain home-
cluding bulk flow at the B-NC interface [21], via other dura mater ostasis of the interstitial fluid of the medial temporal pole [21]. CBT-AD
lymphatics [160,161], via glymphatic clearance [22] or by way of fa- as advocated here is different than what is currently practiced; now, we
cilitated transport at the blood-brain barrier [196]. We posit that this mostly render palliative care for those with advanced AD. Thus, beha-
redundancy, along with immune processes [4], usually prevents an vioral therapies, or training, aimed at olfaction, sleep, exercise, atten-
accumulation of proteins in interstitial fluid thereby sustaining the tion to diet and/or practicing specially designed computer-assisted
homeostasis characteristic of a healthy, youthful brain. Presumably, game-like programs may be a feasible avenue toward reducing the risk
these various processes are responsive in varying degrees depending on and morbidity of Alzheimer’s disease.
the changing status of the constituents of fluids reaching the brain (e.g.,
due to what has been eaten recently) and what an individual is doing Declaration of interest
(e.g., sleeping or dancing). When one means of clearing excess protein
from the brain is sluggish, overwhelmed or otherwise inoperative, the The authors have no conflicts of interest to report.
other ways would become more salient to health. However, reduction
in efficiency of one means of clearing the brain of excess protein (e.g., Funding source
disease at the B-NC) puts the individual at great risk when another
means of clearing excess protein is not functioning optimally (e.g., poor This research did not receive any specific grant from funding
sleep habits). The implication is clear: to develop some insurance to- agencies in the public, commercial, or not-for-profit sectors.
ward having a healthy brain throughout retirement age, it seems ra-
tional to engage activities that reduce multiple risks for developing AD. Acknowledgements
That is: maintain what is currently extant as a healthy lifestyle (features
of gross activity and diet) and also attend to risks that may not usually The authors wish to thank the many students, past and present, who
be considered as critical such as practicing olfactory perception, at- have contributed to this work.
tending to habits of sleep, and practicing brain training.
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