Does Deep Purpose Diminish the Risk of Alzheimer Dementia?

Abstract

Aging does not equal becoming demented. There is much interpersonal variance apart from genetics. Healthy habits are seen as part of the reason. Obviously, the mind itself is involved. Although not considered in many studies and risk scores, deep purpose may be used as a central concept. A person without it has no incentive to keep a sharp mind, as is obvious to. many people in everyday life. In this perspective article, deep purpose is put in relation to other risk factors such as depression, neuroticism and stress, also showing its possible use for diminishing the sporadic Alzheimer scourge. The goal is Alzheimer-protection. Heightening deep purpose from the cradle to the grave is also relevant to lifelong intellectual prowess.

Full text

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Does Deep Purpose Diminish the Risk of Alzheimer Dementia?
Jean-Luc Mommaerts, MD, MSc, PhD
Abstract max 150 words
Aging does not equal becoming demented. There is much interpersonal variance apart from genetics.
Healthy habits are seen as part of the reason. Obviously, the mind itself is involved. Although not considered
in many studies and risk scores of dementia, including Alzheimer, deep purpose may be a central concept.
A person without it has no incentive to keep a sharp mind, as is evident to many people in everyday life. In
this perspective article, deep purpose is put in relation to other risk factors such as depression, neuroticism,
and stress, also showing its possible use for diminishing the sporadic Alzheimer’s scourge. The goal is
Alzheimer protection. Heightening deep purpose from the cradle to the grave is also relevant to lifelong
intellectual prowess.
1. Introduction, room for the mind ....................................................................................................... 1
2. A lesson from Alzheimer’s brain ........................................................................................................ 2
3. About deep purpose (DP) .................................................................................................................. 3
4. From lack of deep purpose to Alzheimer .......................................................................................... 3
5. Practical implications to Alzheimer-protection ................................................................................. 5
6. Research questions............................................................................................................................ 6
7. Conclusions ........................................................................................................................................ 6
8. Addendum: Aducanumab.................................................................................................................. 6
9. References ......................................................................................................................................... 8
In this text, ‘Alzheimer’ refers to ‘Alzheimer Disease of the sporadic (late-onset) type,’ whether or not it
is eventually appropriate to call it a disease.
Abbreviations
DP: deep purpose
1. Introduction, room for the mind
In 2020, there are 5.7 million cases in the US, and 50 million worldwide, costing $300 billion.(1) By 2050, a
projected 13 million people will have Alzheimer in the US [(2), p89], and 150 million worldwide. (1) Note

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some relativity of these numbers since there are continua between the normal, the aging, and the
Alzheimer brain, as well as between Alzheimer and other degenerative forms of dementia (frontal lobe,
Lewy body…).
Not all elderly persons develop dementia. Quantitative studies show that healthy brain aging is possible
for up to 89 years. (3) Up to 25% of centenarians show functionally intact cognition. (4) Above 90 years of
age, some cognitive decline may be inevitable. So, if we live long enough, will we all be demented? Maybe,
but one can contemplate what is ‘decline.’ Some of it may better be called ‘change,’ or even ‘growth’
depending on the viewpoint and how the person with mild Alzheimer handles his condition. Interesting in
all this is Alzheimer’s cognitive resilience, an intact cognitive function despite typical neuropathological
features (plaques, tangles). (5) There is a positive correlation to a college degree. (5) Meanwhile, genetic
factors such as APOE€4 do not significantly influence cognitive decline (or resilience to it) on top of
neuropathic lesions.
Altogether, this leaves ample room for mental causative factors. In this, the most crucial question is
whether DP can be framed pragmatically to make a difference.
Working on DP is especially important for the lack of ongoing therapeutic success (no substantial positive
impact on prevention or reversal of cognitive decline) with disease-modifying drugs in affecting disease
progression compared with placebo despite many clinical trials (200 drugs in phase 2). The most recent
approval of a new anti-Alzheimer drug was a decade ago (from 2019). (6) Currently, the only available
treatments are symptomatic. (7) A much-contested exception might be Aducanumab: see addendum.
Repeated claims that there will be a cure within five years have been made for a long time but are still
unrealized. (8) Also, there is no objective evidence that drug candidates work better when given earlier.
(8)
2. A lesson from the Alzheimer brain
A primary Alzheimer-culprit is seen in the Amyloid-beta protein forming plaques that devastate neuronal
and synaptic functions. The search for drugs has been oriented against this protein. However, its
accumulation is part of an ‘amyloid cascade.’ (8) This can be seen as a chain of stress and other responses,
whereby the levels of Amyloid-beta are highly regulated in response to many upstream factors. The real
Alzheimer toxicity may be occurring upstream, making amyloid-oriented therapeutic strategies
oversimplified. (9) The question is, “What disturbs the equilibrium toward plaque formation?” Therefore,
a related question is whether we will ever find a satisfactory way to influence Alzheimer through Amyloid-
beta or any other downstream factor.
Small increases in Amyloid-beta may enhance memory formation; higher increases may lead to a long-
term downgrade. Amyloid-beta production can thus, in principle, be a physiological response to stress or
injury, whereby an increased production may even be neuroprotective, getting a damaging effect at a later
stage.
We need greater emphasis on more upstream factors in Alzheimer. However, we may find this is less
mechanically reducible, more into the realm of complexity. The view of ‘solving a very complicated
problem’ (such as comparing it with polio eradication) is principally flawed. A war metaphor (fighting the

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disease, war on amyloid) has little place. Even more so since individuals with numerous amyloid plaques
do not necessarily have clinical dementia. [35 in A22]
***
David Eagleman neurocognitive: mental-neuronal patterns (MNPs); mind=body paradigm. In terms of
these patterns, purpose can be seen as congruence → relevance of empathy, especially when deeply felt
→ ‘empathy beyond’
3. About deep purpose (DP)
In this text, ‘purpose’ is (vaguely) conceptualized as what draws people in the long term toward a
meaningful goal. It may be anything from having a world-changing goal to caring for a grandchild, a pet,
or a plant on the windowsill. DP underlies any such desire. Thus, a person can say, “My life has a purpose”
concretely, or “My life has purpose” without any graspable object of this purpose. A person can more or
less have a predisposition toward DP to the degree that he readily finds/feels/shows such a meaningful
desire. This may be co-determined by a genetic predisposition.
DP is elusive by necessity. Nevertheless, people talk about it as meaningfully important. Even more, it is
an essential part of life for many. We can/should thus use the concept in communications, also concerning
Alzheimer. For instance, lack of DP is part and parcel of depression, of which the prevalence is much higher
in dementia than in the general population. (10)
A useful framework is the concept of ‘cognitive reserve’ (or the reverse ‘cognitive debt’ (11)). Stern
discerns in this a passive component (capacity one brings to old age) and an active one (ability to adapt).
[(12) p.453] Although this concept may hold, its effect may be superseded by purpose. People do not
strictly need to be intelligent (educated…) to avoid Alzheimer (in contrast to age-related cognitive decline).
Also, intellectually less-stimulating cultures do not show more people with Alzheimer (REF?). Living close
to nature may enhance DP and be Alzheimer-protective. Nevertheless, DP will follow suit in a culture that
values intellectual achievement. In an intellectual environment, individuals with high DP will more readily
strive for higher education. Does the Alzheimer protection then come from schooling, underlying DP, or
both?
DP lies at the body-mind intersection, more precisely, body=mind. This contrasts with conceptual purpose,
which is an abstraction ― thinking/talking about something that exists only conceptually. Conceptual
purpose is an epiphenomenon. Working only at this level may not change much mentally or physically.
DP is one’s zest for life. Note that life and purpose came together from the start of life itself. Even a
bacterium had the purpose of surviving and thriving, albeit in its primitive form. Without purpose, it would
be a non-living mechanism. From there, purpose followed the chain of evolution right up to us. It may be
our most essential element. No wonder it can have a substantial impact on cognition.
4. From lack of deep purpose to Alzheimer
In his report of the classic Nun Study (678 Catholic sisters, followed from 1991 till 2002), D.A. Snowdon
describes sister Mary (among others) as a gold standard for successful cognitive aging. Despite abundant
Alzheimer lesions (plaques, tangles, atrophy) at autopsy, she had “high cognitive test scores before her

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death at 101 years of age.” Despite the critique of the study (13), sister Mary stands as a reminder of what
is possible in old age “with grace, joy, and beauty.” (14) Note that, as a devoted believer, she had DP almost
as a ‘gift of God.’ However, non-believers should not be left in the cold, even more since purpose is central
to life itself. That, and the impact of being a believer on mental and physical health, may explain its
attractiveness in any form.
A lack of DP leads to a chronic imbalance between wanting and being-able-to, leading to stress. (The
perception of) stress can thus be seen as anything that obstructs DP, eventually jeopardizing it, flowing
into burnout. Stress correlates with hypertension, atherosclerosis, diabetes, and many other noted risk
factors for Alzheimer. It may also directly influence Alzheimer-related elements. This is being successfully
investigated at the structural, cellular, and biochemical levels (plaques/tangles, volume of hippocampus),
although time-length and variable resilience levels complicate studies. (15) In rats, this has been shown
with even mild chronic psychosocial stress. (16) Neuroticism (including vulnerability to stress, depression,
and angry hostility through thwarted purpose) has been consistently and strongly implicated as an
Alzheimer risk factor in humans. (11)
A review of human and animal studies indicated that chronic stress is a significant risk factor for Alzheimer.
(17) In one study over five years, 90th percentile of high stress-proneness showed twice the risk of
Alzheimer compared to 10th percentile of low stress-proneness (Wilson et al 2003 in A23)
Early life adversity accelerates cognitive decline at a later age and vice versa. How this happens
(neurobiological mechanisms) remains elusive, possibly through cellular defense mechanisms, better
repair responses, higher brain plasticity (recruiting other brain circuits, leading to alternative strategies),
and a higher number of neurons and synapses. (18) This brings Alzheimer close to a psychosomatic
condition. In rodent studies, the early postnatal period is a sensitive phase influencing vulnerability to
Alzheimer development. (18) In humans, early life until adolescence is a sensitive time for environmental
factors influencing the risk of developing Alzheimer. [28 in A26] For instance, in one study, adolescents
experiencing parental death before 18 years of age showed a higher risk of cognitive decline at a later age.
[113]
Distinguishing between depression and Alzheimer can be challenging. Apathy is common in depression
and dementia. This is the lack of motivation evidenced by diminished goal-directed motor behavior,
cognition, and emotion (10). It can be straightforwardly seen as the opposite of DP. A narrative review
showed convincing evidence (dose-response relationship) that depression and dementia are correlated,
with (early life) depression as a risk factor or (late life) depression as a prodrome. There are similar
neurobiological changes in depression and dementia, pointing to shared risk factors or neuronal damage
patterns. Depression remains an independent risk factor even in studies that controlled for shared risk
factors. (19) Thus, a shared pattern of neuronal damage is probable.
Repetitive negative thinking has also been related to several Alzheimer risk factors and to Alzheimer itself.
(11) One can see an attempt to get beyond a felt lack of DP.
On the other hand, DP has several positive influences, such as adopting a healthier lifestyle, which is
Alzheimer-protective. Other related characteristics of DP may also be positive: heightening stress
resistance, lowering nocebo, inviting body/mind hygiene, and intellectual activity, which may lead to
higher resilience and less cognitive decline despite lesions.

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5. Practical implications to Alzheimer-protection
DP is not considered in many studies and risk scores (20). For instance, the FINGER study in Finland is a
largescale, long-term RCT [150, 151 in A7] on nutrition, exercise, cognitive training, social activities, and
vascular and metabolic hygiene, showing the benefit of these on cognition also in Alzheimer. (21) DP was
not included. Another study found that higher education, healthy diet, social and physical activities, a
positive early life environment, maternal care in rodents (licking, grooming), and lifelong mental
stimulation positively influenced memory decline, while there was a negative influence of prolonged stress
and depression. (18) Note here also the absence of DP, although it may be related to several factors.
As implicated above, there is a positive association between spirituality/religion and brain health [4 in
A14], recognizing spirituality as helpful in the quest for purpose in life. [19 in A14] Notably, purpose in life
reduces Alzheimer risk up to 2.4 times, apart from other risk factors. [103 in A14] It also heightens
successful aging in general. [109 in A14] Bringing DP to the elderly may thus be Alzheimer-protective. This
cannot generally be done through pampering but by stimulating. More activity of the elderly, such as
participating in frequent leisure activities, brings a 38% lower risk of Alzheimer. [111 in A26] On top of
protection, DP may also aid the Alzheimer patient in coping with his condition, as has been shown in the
context of spirituality, probably mainly through providing a higher/more profound sense of relationship.
(2)
Is the brain generally vulnerable to Alzheimer because of its flexibility, especially in learning/memorizing
what we do all the time? Plaques and tangles may inhibit the formation of the above-mentioned mental-
neuronal patterns. In this case, the flexibility may as well be put to good use. DP may bring congruence in
the ‘society of mind.’ Does this make it easier for the brain to clear excessive debris?
A quicker deterioration of Alzheimer by depression and stress has been noted. [p.801 in A16] Thus, factors
that protect against depression may also be Alzheimer-protective. One of the most important protective
factors may be DP. This may explain the conflicting results of treating depression-as-such on reducing the
risk of cognitive impairment. (19),(10)
Although meditation increases the grey matter volume in the hippocampus in normal subjects, (22) little
is known about the influence of meditation on Alzheimer. The only published longitudinal RCT on
meditation in this field shows a delay in deterioration of cognitive capacities in mild to moderate
Alzheimer. [Quintana-Hernandez, 2016 in A16] Other studies do not exceed eight weeks, which may not
be long enough to show any influence in case there is one.
Unfortunately, “Nearly all of my AD spousal support group members indicated that their doctors also
provided no helpful information upon diagnosis ... Such a lack of communication from doctors is
inexcusable … Meeting regularly with other people who ‘‘get it’’ can be incredibly empowering and
emotionally supportive at the same time.” (23) Such a group may replenish DP.
Childhood education in DP is probably an important factor in Alzheimer protection in old age. DP is
important in children’s education. If a child learns it early, this lesson may last a lifetime. If not, one can
develop it later, although probably less spontaneously. Therefore, stimulating early life experiences are
important.
Moreover, the pre-symptomatic phase of Alzheimer may take 20 years or more. (20) This leaves ample
time for more concentrated Alzheimer protection in those at risk from midlife onward. Important in this

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is the improved early diagnostic accuracy of Alzheimer in the last several years. [ALZH-Wietse] However,
since no disease-modifying treatment exists, communicating an early diagnosis is also an ethical question.
This may be relieved by bringing to bear DP. The communication then becomes a very human and humane
one. Moreover, if (much-needed) studies show a genuinely positive influence of DP on Alzheimer-
protection, it would be unethical not to strive for an early diagnosis.
6. Research questions
These are some research questions that flow from the above:
• It would be interesting to see whether plaques and tangles can be avoided through DP, or cognitive
decline, or both separately.
• What is the correlation between one or more episodes of substantial burnout during a lifetime
and earlier onset of Alzheimer?
• What is the true placebo effect of anti-Alzheimer drugs? What can we (or perhaps not) learn from
previous RCTs about this?
• Should Alzheimer be seen as – partly – a compensatory overshoot through lack of DP?
7. Conclusions
We witness an evolution in the view of Alzheimer from a disease of old age toward a life course perspective
in which the degree of having deep purpose (DP) may be determinant for intellectual evolution and
Alzheimer protection. This makes DP important from womb to tomb, despite not being easily graspable.
A spiritual dimension is involved that may be independent of religion. This should be further clarified. We
hope the (fuzzy) concept of DP can help in this. Finally, we note that heightening DP may need wise support
more than professional, knowledge-based, resource-intensive interventions.
8. Addendum: Aducanumab
Aducanumab, a monoclonal antibody, was FDA-approved (‘accelerated approval pathway’) in June 2021,
with the intention to market at 56.000 USD per year. Aducanumab is administered per IV injection every
month. It has substantial side effects, such as brain edema (35% of cases), hemorrhages, headache,
siderosis, falling, diarrhea, confusion, and delirium. It only works at a high dose, with a small and
incoherent effect on cognitive function. Of the two studies on cognitive function, its impact vs. placebo is
absent in one study and statistically significant in the other mainly because of the inter-study difference in
the placebo arms. It is not known where this difference comes from. Note that side effects may bring
substantial bias to RCTs, especially in placebo-prone domains. (24) With hardly any evidence that
aducanumab can restore memories or cognitive function, the FDA approval is based on reducing beta-
amyloid plaques. It is, therefore, as to the vein of this article, not an anti-Alzheimer but an anti-amyloid
plaque treatment.
In the course of my PhD, I published a study about the influence of treatment
assumptions (TA – subjects guessing their allocations) engendered through placebo vs.
methylphenidate on cognitive function in healthy young adults. [Psychol Res Behav
Manag, 2013] The study showed a significant effect of TA. I also wrote an article on Serial

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Treatment Assumption Testing (STAT, own term). In this, I argued that many double-blind
studies might become much less double-blind when STAT is brought to bear. Subjects
correctly guess their group allocation in a study based on side effects and more.

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9. References
1. Khalsa DS, Newberg AB. Spiritual Fitness: A New Dimension in Alzheimer’s Disease Prevention. J
Alzheimers Dis JAD. 2021;80(2):505–19.
2. Beuscher L, Beck C. A literature review of spirituality in coping with early-stage Alzheimer’s
disease. J Clin Nurs. maart 2008;17(5A):88–97.
3. Morris JC. Is Alzheimer’s disease inevitable with age?: Lessons from clinicopathologic studies of
healthy aging and very mild alzheimer’s disease. J Clin Invest. november 1999;104(9):1171–3.
4. Perls T. Centenarians who avoid dementia. Trends Neurosci. oktober 2004;27(10):633–6.
5. Aiello Bowles EJ, Crane PK, Walker RL, Chubak J, LaCroix AZ, Anderson ML, e.a. Cognitive
Resilience to Alzheimer’s Disease Pathology in the Human Brain. J Alzheimers Dis JAD. 2019;68(3):1071–
83.
6. Cummings JL, Tong G, Ballard C. Treatment Combinations for Alzheimer’s Disease: Current and
Future Pharmacotherapy Options. J Alzheimers Dis JAD. 2019;67(3):779–94.
7. Loi SM, Eratne D, Kelso W, Velakoulis D, Looi JC. Alzheimer disease: Non-pharmacological and
pharmacological management of cognition and neuropsychiatric symptoms. Australas Psychiatry Bull R
Aust N Z Coll Psychiatr. augustus 2018;26(4):358–65.
8. Whitehouse PJ. The end of Alzheimer’s disease--from biochemical pharmacology to
ecopsychosociology: a personal perspective. Biochem Pharmacol. 15 april 2014;88(4):677–81.
9. D’Alton S, George DR. Changing perspectives on Alzheimer’s disease: thinking outside the
amyloid box. J Alzheimers Dis JAD. 2011;25(4):571–81.
10. Gutzmann H, Qazi A. Depression associated with dementia. Z Gerontol Geriatr. juni
2015;48(4):305–11.
11. Marchant NL, Howard RJ. Cognitive debt and Alzheimer’s disease. J Alzheimers Dis JAD.
2015;44(3):755–70.
12. Snowdon DA, Nun Study. Healthy aging and dementia: findings from the Nun Study. Ann Intern
Med. 2 september 2003;139(5 Pt 2):450–4.
13. Weiner MF, Cullum CM, Rosenberg RN, Honig LS. Aging and Alzheimer’s disease: lessons from
the Nun Study. The Gerontologist. februari 1998;38(1):5–6.
14. Snowdon DA. Aging and Alzheimer’s disease: lessons from the Nun Study. The Gerontologist.
april 1997;37(2):150–6.
15. Mravec B, Horvathova L, Padova A. Brain Under Stress and Alzheimer’s Disease. Cell Mol
Neurobiol. januari 2018;38(1):73–84.
16. Alkadhi KA. Chronic psychosocial stress exposes Alzheimer’s disease phenotype in a novel at-risk
model. Front Biosci Elite Ed. 1 januari 2012;4(1):214–29.

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17. Machado A, Herrera AJ, de Pablos RM, Espinosa-Oliva AM, Sarmiento M, Ayala A, e.a. Chronic
stress as a risk factor for Alzheimer’s disease. Rev Neurosci. 2014;25(6):785–804.
18. Vulnerability and resilience to Alzheimer’s disease: early life conditions modulate
neuropathology and determine cognitive reserve - PubMed [Internet]. [geciteerd 24 mei 2022].
Beschikbaar op: https://pubmed.ncbi.nlm.nih.gov/30227888/
19. Bennett S, Thomas AJ. Depression and dementia: cause, consequence or coincidence? Maturitas.
oktober 2014;79(2):184–90.
20. Imtiaz B, Tolppanen AM, Kivipelto M, Soininen H. Future directions in Alzheimer’s disease from
risk factors to prevention. Biochem Pharmacol. 15 april 2014;88(4):661–70.
21. Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, e.a. Alzheimer’s
disease. Lancet Lond Engl. 24 april 2021;397(10284):1577–90.
22. Russell-Williams J, Jaroudi W, Perich T, Hoscheidt S, El Haj M, Moustafa AA. Mindfulness and
meditation: treating cognitive impairment and reducing stress in dementia. Rev Neurosci. 25 september
2018;29(7):791–804.
23. Vann A. Empowering people with Alzheimer’s disease and their caregivers--there is still much
work to be done. Dement Lond Engl. maart 2013;12(2):155–6.
24. Mommaerts JL. Lack of blinding in a cloud of unknowing: What remains of antidepressants’
effectiveness? Psychiatry Res. 1 juli 2022;313:114609.