Alzheimer's disease (AD) has been most intensely studied over the past two decades and a great deal of research papers published, yet its pathological cause has remained unknown. Recently, our experimental and theoretical studies (1-3) have suggested that the mechanism of origins of AD may not be overly complicated if we keep an open mind to some basic questions. These questions are discussed below.
Q: What causes AD?
A: Let's put it this way: Dementia in the elderly used to be rare, but why has it become a major social threat today? There can be numerous potential answers, but an ultimate one should be clear: while the elderly used to live to age 60 or 70, today many of them live into their 80s and 90s. Using this fact as the starting point for reasoning, then it would be clear that "advanced aging" would be a primary suspect in senile dementia (4-6).
Q: Longevity is what we all want and aging is only a risk-enhancing, or minor, factor in age-related diseases. How can it become a "primary" factor in senile dementia?
A: Aging will progressively deteriorate the functions of cells/organs. This is not a problem in its early stages; but if it progresses into an unprecedented advanced stage, aging will severely undermine the viability of cells/organs, leading to their death in the end -- just as our heart will eventually fail.
Human life expectancy is determined by the states of vital organs (heart, liver, lung, etc.), but vision, hearing, and higher cognitive function of the brain are not vital for life (they determine the quality of life). Now, the lifespan of the vital organs has been substantially extended but that of the non-vital ones has not in the same period. As a result, the latter organs' failures will become increasingly common in the oldest-old people today.
Q: This was an old view, but abandoned long ago, because it did not explain why many other elderly can remain perfectly healthy at the same old age. This allows us to redefine senile dementia as a disease just like AIDS or cancer (7). If only some people are affected at the same old age, then there must be a pathogen, in addition to aging, to explain the disease. It is a law of medicine that diseases are caused by pathogens and, therefore, Alzheimer�s disease must have a pathogenic factor. This pathogenic factor is usually mutant genes, infectious agents, metabolic errors, environmental toxins, etc.
A: While it is correct to assume that a factor or factors in addition to aging might explain the individual specificity of senile dementia, this factor(s) may not always be one of those conventional pathogens. Let's consider other senile diseases. For instance, aging will cause the heart to fail, but why can some people live to age 100 whereas others die in their 80s? Also, elderly commonly have bone loss and muscle weakening, but why do only some of them develop clinical osteoporosis and muscle atrophy at the same age?
After numerous studies, it is clear today that most of these cases can be explained, not by pathogens, but mainly by the so-called "risk factors" in life (lack of exercises, certain diets, alcoholism, individual background, etc.) (8). These factors are not critical in young people, but in the oldest-old persons, they can act like the last straw upon an overburdened camel. Indeed, it seems to be a general pattern that advanced aging will predispose the elderly to a wide variety of senile disorders, whereas other risk factors will largely determine the onset age and individual specificity of their clinical manifestations.
Based on this reasoning, it seems likely that many, if not all, cases of senile dementia might also be explained by �advanced aging plus risk factors� (3). These cases are more precisely called "late-onset AD", which typically occurs around age 80 and are clinically diagnosed by excluding apparent causes such as vascular diseases, head trauma, and other known causes. Defined this way, then late-onset AD would be perhaps the only type of dementia with unknown initial cause, but threats the society most severely today.
This model for late-onset AD can also be compared to those for some other peculiar disorders. For example, modern lifestyle is known to be responsible for the widespread occurrence of obesity, diabetes, atherosclerosis, and other "luxury diseases" -- despite that not everyone is affected under the same living conditions. Together, these modern disorders may impact our traditional perceptions of human diseases.
Q: Any conditions causing human sufferings and social burdens are diseases, why are senile disorders so different from other diseases?
A: Senile disorders occur only at the end stages of longevity, unlike conventional diseases that can strike us at any age and they are caused by invading or inherited pathogens (e.g., AIDS, cancer, polio, epilepsy, Down's syndrome, etc.). The two groups of illness have similar symptoms and social impacts (care cost, family burden, human suffering, etc.), so they are both called �diseases� by us. But it must be noted that they differ profoundly in medical nature (origin, prevalence, onset age, intervention strategy, etc.). As such, ignoring these differences would lead to confusion in the search for their respective etiologies.
Using an analogy, conventional diseases are like the failures of new or middle-aged cars, which must involve manufacturer error or accident. But senile disorders would be like the failures of very old cars. Although both failures have similar consequences, their causations are quite different. This may be why after intensive studies for decades, no common pathogen (like HIV in AIDS) has been found in late-onset AD (nor in senile osteoporosis, muscle atrophy, or senile cataracts).
Q: A pathogen not found does not mean it does not exist. How do you know it will not be found in the senile dementia patients in the future?
A: If a pathogen strikes us, it will occur in low incidence. This is because the probability of our defense systems that are overtaken by a pathogen must be low, so conventional diseases usually affect no more than a small percentage of the population. Remember, this is the main reason we call them "diseases" (exceptions from majority/normality).
But senile dementia is quite different. Its prevalence doubles every 5 years after age 60 and surpasses the 50% landmark by age 85 or 90 (3, 8), as is also the case of other senile disorders. It should be pointed out that when tragedy affects the majority of people by certain age as a pattern, it may not be an "accident" anymore (thus not a "disease" in its common sense). Rather, it may be taken as an "expected" or even "normal" event (like heart failure at advanced age, or eventual death of the car). Evidently, such cases may not be explained by a pathogen/accident as its common cause (though pathogens can be involved in some individuals).
Q: AIDS can also affect nearly 50% of the people in certain communities, but why is it a conventional disease?
A: A conventional disease will also involve a new pathway that is independent of normal metabolisms (such as HIV proliferation or cancer outgrowth). Hence, AIDS or cancer is �all-or-none" in an individual. But senile atherosclerosis, osteoporosis and memory decline occur to a certain extent in all elderly. Although some people develop into clinical stages but others do not, this classification is based on quantitative parameters, not on the existence of a new pathway.
In other words, these patients have developed pathologies but not necessarily through �pathological� pathways as in conventional diseases. Rather, the pathologies can occur if natural aging process develops to extreme. If bodily functions progressively decline as aging advances, then logically, our heart, bone and brain will eventually fail.
Q: This may be true for the heart, but is it also true for the brain given that so many elderly have perfect cognition by the time they die?
A: In the dead old cars, we can always find some functioning radios. Does that mean that those radios will work forever?
Q: Even though the brain may die by natural course, it should occur after 120 years because healthy individuals of that age do exist. If they represent normal lifespan of our brain, then typical AD today (around age 80) should be a conventional disease (7). Is this popular view correct?
A: Healthy centenarians are rare, so they are an exception rather than representative of the general brain lifespan. In reality, the prevalence of dementia has surpassed 50% by age 90 in the population (3). This fact may allow us to deduce that human brain will not last forever, but like any other organs, has a limited lifespan. This lifespan today is perhaps about 90 years on average (similar to the way we define the average life expectancy: the age at which half of the people are dead; it is about 75 years in the U.S. today). This means that brain lifespan on average is only about 15 years longer than the lifespan of vital organs. This can explain why most people do not develop dementia in real life, but those who live beyond age 80 are exponentially affected.
Q: There is another problem: Many conventional diseases are caused by gene mutations, and several mutant genes have been proven to be the cause for early-onset AD (dementia before age 65). If so, then how can late-onset AD be an unconventional disease if it has the same symptoms as early-onset AD?
A: Because early-onset AD, a rare disease, is fundamentally different from late-onset AD in medical nature. The term "Alzheimer's disease" originally defined the former, not the latter, based on their onset age difference. But since 1970s, the two conditions have been redefined as the "same disease" on the basis that they display the same symptoms and hallmarks (plaques and tangles). According to this new definition, if early-onset AD is caused by gene mutations or other pathogens, then late-onset AD must have a similar cause.
However, upon careful considerations, we now realize that this definition itself is problematic. Although many diseases are correctly defined by pathologies but not by a patient's age (such as AIDS, pneumonia, influenza, etc.), not all diseases can be defined in this way. For example, juvenile-onset atherosclerosis can be caused by rare gene mutations (on LDL receptors) and it displays the same hallmark of senile atherosclerosis (cholesterol deposition). But it is obvious that this "same" deposition in most senile cases is not due to gene mutations, but aging. Other similar "pairs" of human diseases are also known to have different causes: juvenile cataracts vs. senile cataracts; juvenile/midlife hearing or vision loss vs. senile hearing or vision loss, etc. (8, 9).
So, generally speaking, if a disorder occurs in juvenile or middle-aged, it must be caused by a pathogen, like heart failure at midlife. But if the "same" tragedy occurs in very old people, then the cause may be quite different. In other words, changes originated for different reasons can lead to the same hallmarks and symptoms. Clearly, had their onset age difference been ignored, then the quest for the causes of senile disorders would have been confused.
Similarly, rare gene mutations can cause amyloid deposition in early-onset AD, but the "same" amyloid deposition in most elderly is obviously not due to gene mutations. Thus, defining senile and midlife dementia as the "same disease" based on the hallmarks only, but not onset age, may be an initial mistake. This new definition has successfully aroused the public and Congress to enthusiastically support research (4, 5), but at the same time, it has inconspicuously converted a senile condition into a conventional "disease". Thus defined, aging-related cognitive decline would be conceived as "pathogen-triggered," and aging study would give way to "pathogen hunting". This has profoundly changed the direction of scientific inquiry to miss the main target.
If old car's failure is officially defined as the same as young car's, and large amounts of research funding are assigned to it, will researchers, therefore, eventually find the same errors in the old car?
Q: But how can this definition be accepted by almost all researchers today if it is incorrect?
A: This may be a difficult question. Alzheimer research is driven mainly by fear. As projected, the number of the victims will soon multiply and this will disable the families and even bankrupt government. To such a devastating national disaster, one would naturally expect that finding a cure would be our only hope. And for this hope to be justified, the disorder must rather be considered a "disease" (thus curable) than a senile condition (irreversible). After all, it seems logical that pathogens cannot be excluded without thorough investigations.
Once late-onset AD is defined as a conventional disease and sometimes even called "independent of aging" (7), and this definition has become an authoritative government guideline for research funding (4, 5), most scientists would have no choice but to use it as the starting point for reasoning. Along this line, a central question would be: "Why do cells die" (7)? When the question is posed this way, pathogens would be the only answer.
However, if it is defined as a senile condition, then the central question would become: "Why do the oldest-old cells die"? Had it been asked this way, the answers may have been quite different (10, 11).
Q: Although most patients do not have gene mutations or infectious agents, they do have a common toxin: amyloid. If a toxin exists, then whatever theory is, senile dementia would still be a conventional disease that will be cured if amyloid is targeted.
A: Amyloid deposition is a natural event during aging, like cholesterol and mineral depositions in various tissues. It starts at about age 50 in essentially everybody (12), but dementia does not typically strike until ages 70-80. So, if it is amyloid that kills cells, it is taking 20-30 years to do so. And even by age 80, most people are healthy. This indicates that the effect of amyloid must be so mild that it can only increase the probability of cell death to a certain extent even after three decades of action. Now, is it appropriate to call such a substance "toxic"?
The term "toxic" describes the acute and outright killing ability of pathogens such as HIV, arsenic, or mercury. But the action of amyloid is more like other age-related lesions (tangles, lipofuscins, cataracts, cholesterol, etc.). They all are negative and eventually can be harmful, but not toxic in molecular nature. Once called �toxic�, amyloid would be singled out as a bona fide pathogen and senile dementia would become a conventional disease.
Q: Even if amyloid is not an acute toxin, it may still be a slow toxin like cholesterol and gallstones that can cause severe diseases when overly deposited. May this be the case?
A: Cholesterol and gallstones can obstruct circulation systems, so the diseases they cause have an abrupt onset after a long accumulating process. But amyloid plaques deposited outside neurons do not seem to have such an effect, because no similar acute symptom is seen in the progressive and insidious senile dementia (amyloid deposits on the blood vessel walls may affect blood flow, but they are minor compared to cholesterol).
Although plaques and tangles are deposited at a faster rate thus are more abundant in dementia patients than in other elderly, this may also be explained by risk factors -- again similar to the faster cholesterol and mineral depositions in some people. If cholesterol and mineral depositions result from slowed degradation and clearance in aging, but not due to any �metabolic errors�, then plaques and tangles would have a similar origin (i.e., protein turnover slowdown).
Even if overly deposited or denser plaques kill cells, it will take additional years/decades for them to reach this stage. Thus, this concept is, in essence, the same as saying that advanced aging is a primary culprit. However, over such a long period, not only amyloid but also other aging-dependent lesions (energy decline, hormone and growth factor depletion, free radicals, etc.) will all reach critical stages and contribute to cell death. Thus, unlike AIDS study which can be reduced to "HIV study", senile dementia study may not be reduced to "amyloid study" only, even though we all eagerly hope that a conventional pathogen can be found.
Q: This theory would mean that senile dementia would be hopeless because we do not have a pathogen/error to get hands on, so how can we accept it?
A: Pointing out that old car will eventually fail does not mean we cannot make it work longer. But this needs a "new" concept; that is, to preserve or extend the functional lifespan of the brain to match that of other organs -- a task quite different from curing pneumonia by penicillin. If the lifespan of many other organs has been successfully extended, then why can't the brain's lifespan?
Q: But how?
A: By focusing our attention on advanced aging and risk factors. The viability of old nerve cells will diminish along with a progressive deprivation of life-supporting factors such as growth factors. This is perhaps the ultimate reason for the accumulation of various age-dependent lesions (1). Thus, at the present time, replenishing these vital factors is an important approach to slowing down neurodegeneration, i.e., doing for the brain just as what we have done to old bones and muscles.
Q: Growth factors, vitamins and hormones are long known, but they only have very limited effects. How can we place our hope in them?
A: This is because such drugs, when delivered through ordinary routes, may not reach the brain (blood brain barrier), and also because of their short-term actions vs. an extra-slow illness and side-effects (e.g., hormone increases the risk of breast cancer).
These problems would call for a revolutionary drug-delivery method that will ensure the brain-specific and extra long-lasting effects of the drugs. It has been reported that transplanting cells carrying genes for nerve growth factor into animal brain has slowed down age-related neurodegeneration (13). If practical obstacles can be overcome, studies along this line may offer new promise. It is also possible that a "cocktail" of several neurotrophic factors or rate-liming elements in their synthesis pathways, rather than a single one as currently used, may be more effective.
Q: What else can we do?
A: To avoid risk factors in life (sedentary lifestyle, unhealthy diets, social isolation, low brain reserve, depression, etc)(4). Among them, perhaps the most common and important one is lifestyle (14, 15), because the functional lifespan of the old brain, like that of old muscles, critically depends on its usage ("use it or lose it"). But unlike muscles, brain usage by the elderly further depends on a supportive social network. Our aging population is in unprecedented longevity, thus equally unprecedented social supports are urgently needed.
Current social security systems and supportive practices such as visiting the elderly once a year may have successfully taken care of them in their 60s or 70s, but may not be enough today. Calling or visiting our elderly as frequently as once a week or more, for instance, may be necessary for those in their 80s and 90s where social isolation is common. Special opportunities should also be provided for them to tell their early-life stories or enjoy old songs, movies, etc. These activities can activate old memories that are associated with basic living abilities.
Such social supports call for the participation of society as a whole, and they should be part of a national awareness program. Such supports will not in and of themselves "cure" senile dementia, but will help win a few critical years at end-life stages, and will largely relieve our social burdens.
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