Updated 8 May 2002

By Ming Chen (michen@hsc.usf.edu), VA Medical Center, Bay Pines, Florida and University of South Florida. January, 2002

Comments

Based on our experimental and theoretical work for several years (1-3), we now advance a new model for the origin of late-onset sporadic Alzheimer's disease (AD). This model surprised us at first, but it may be a logical outcome, that is if several fundamental questions are reconsidered from new perspectives. These questions are:

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 are numerous potential answers, but an ultimate one should be clear: The elderly used to live to age 60 or 70, but today many of them live into their 80s and 90s. If this knowledge is used as the starting point for reasoning, then "advanced aging" would emerge as 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, so how can it become a "primary" factor in senile dementia?

A: Aging will progressively diminish the rate of basic metabolisms and deteriorate cells/organs. This is not a major problem in its early and moderate 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. So, while aging in general is a risk factor, advanced aging can become a killer at advanced stages.

If advanced aging (typically > age 80) can overtake the lives of vital organs (heart, liver, lung, etc.), then it may do the same to other organs because these organs function by the same basic biological mechanisms. Notably, human life expectancy is determined by the states of vital organs, but vision, hearing and higher cognitive function of the brain, are not vital for life (they determine the quality of life). Now, if the lifespan of the vital organs has been substantially extended but that of the non-vital ones has not in the same period, then what will happen? As expected, the latter organs' failures will become increasingly common in the oldest-old people today.

Q: This was an old view, abandoned long ago primarily because it did not explain a central question: Why can many other elderly remain perfectly healthy at the same old age? If only some people are affected, then there must be a "pathogenic" factor, in addition to aging, to explain the disease (7), and this factor usually includes mutant genes, infectious agents, metabolic errors, environmental toxins, etc.

A: It is correct to assume that a factor or factors in addition to aging might explain the individual specificity of senile dementia, but this factor(s) may not always be one of these pathogens. Let's consider other senile disorders. For instance, aging will cause the heart to fail, but why can some people live to age 100 whereas others die in their 80s? Elderly commonly have bone loss and muscle weakening, but why do only some of them develop severe clinical osteoporosis and muscle atrophy at the same age?

After a number of enormous 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 may not be critical in young people, but in the oldest-old people, they can act like the last straw upon an overburdened camel. Hence, 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 as well as individual specificity of their clinical manifestations.

Based on this reasoning, we propose that in most cases, senile dementia may also be explained by advanced aging plus risk factors (2, 3). These cases are more precisely known as "late-onset sporadic AD" or "senile dementia of Alzheimer type" (SDAT), which typically occurs around age 80 today and are diagnosed mainly by excluding apparent causes such as vascular diseases, head trauma, or infectious agents (8). This type of dementia threatens the society most severely but its cause remains a mystery today.

This model for SDAT can also be compared to the mechanisms of 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" (9) - despite the fact 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, so why are senile disorders so different?

A: Senile disorders occur only at the end stages of longevity, unlike conventional diseases that can strike us at any age and are caused by invading or inherited pathogens (e.g., AIDS, cancer, polio, epilepsy, ALS, Down's, etc.). The two groups of disorders have similar symptoms and social impact (care cost, family burden, human suffering, etc.), and thus, the public calls them both "diseases." But it must be noted that they differ 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 causes are quite different. This may be why after intensive studies for decades, no common pathogen (like HIV in AIDS) has been found in SDAT (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 SDAT patients in the future?

A: If a pathogen strikes us, it will occur in low incidence. This is because the probability that our defense systems are overtaken by a pathogen/error 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 has reached 30-40% after age 80 and surpassed the 50% landmark by age 90 (3, 8), as is also the case in other senile disorders. 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, a "normal" event may not be explained by a pathogen/accident as its common cause (though pathogens can be involved in some specific cases).

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 loss occur to a certain extent in all elderly, and they are progressive and continuous processes. Although some people develop into clinical stages but others do not, this classification is based on quantitative parameters, but not on the existence of new pathways.

In other words, these patients have developed pathologies but not necessarily through pathological pathways as in conventional diseases. Rather, the pathologies can occur if a natural aging process develops into extreme. Thus, although dementia differs dramatically from forgetfulness in terms of social impact, this difference is only quantitative in medical nature (6). If bodily functions progressively decline as aging advances, then 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 130 years (10) because healthy individuals of that age do exist. If they represent normal lifespan of our brain, then typical SDAT today (around age 80) should be a conventional disease (7, 10). 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 the 50% landmark by age 90 in the population (5). These data 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 is only about 15 years longer than the lifespan of vital organs. These numbers can explain why most people do not develop dementia in life, but those who live beyond age 80 are exponentially affected - similar to the exponential increase of vital organ failures after age 65.

Q: There is another big problem in your theory. Many conventional diseases are caused by gene mutations, and several mutant genes have been proven to be the causes for early-onset AD. If so, then how can late-onset AD be an unconventional disease if they are both AD?

A: Because "early-onset" AD (or midlife dementia) 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 both display the same symptoms and hallmarks (plaques and tangles)(4, 5). According to this new definition, if early-onset AD is caused by gene mutations or other severe insults, then late-onset AD would have similar insults.

However, upon careful study of medical literature, we finally come to realize that this definition itself is problematic. Although many diseases are correctly defined only by pathologies and 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 is rather the result of aging. Other similar "pairs" of human diseases are also known: 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" disorder 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, but the onset age generally can distinguish them. Clearly, had this onset age been ignored, then the quest for the causes of senile disorders would have been confused.

Similary, 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, but only aging (1). 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 strongly support the research, but at the same time, it has inconspicuously converted a senile condition into a conventional "disease". Thus defined, aging-induced cognitive decline would be conceived as "pathogen-triggered," thus traditional aging studies would give way to "pathogen-hunting". This has profoundly changed the course of scientific inquiry to miss the main targets.

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 we, therefore, eventually find the same "error" 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 the most difficult question. Alzheimer research is driven mainly by fear. As projected, the number of the victims will soon multiply and this will severely disable the families and society. 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 SDAT is defined as a "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 (11, 12).

Q: Although most patients do not have gene mutations, they do have a common toxin: amyloid. If a toxin exists, then whatever theory is, SDAT 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 gallstone depositions (1). It starts at about age 50 in essentially everyone (13), 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, mercury or anthrax. But the action of amyloid is more like those of other age-related lesions (tangles, lipofuscins, cataracts, cholesterol, etc.). They all are negative and eventually harmful, but not toxic. Once called toxic, amyloid would be singled out as a bona fide pathogen. But if this were the case, then how can most elderly remain healthy after having carried this "pathogen" for decades?

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: While such roles of overly deposited cholesterol and gallstones are clearly seen in the abrupt onset of the diseases they cause, no similar acute symptom, however, is seen in the progressive and insidious SDAT. (This may be because cholesterol and gallstones happen to obstruct the circulation systems, but neuritic plaques and tangles do not.) Although plaques and tangles are deposited at a faster rate and are more abundant in patients than in other elderly, this may also be explained mainly by risk factors, again similar to the faster cholesterol and gallstone depositions in some people.

If overly deposited or denser plaques eventually kill cells, then it will take additional extra 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 will all reach critical levels and contribute to cell death, especially the invisible but cumulative effects of the risk factors (2). 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: Dementia brains also display severe oxidative stress, metal imbalance, DNA fragmentation, cell cycle error, and other damages that are absent in normally aged brains. Are these damages, therefore, the causes for cell death?

A: If the brain will eventually fail, then those damages, the end points of life, will eventually occur. Thus, the right question to ask should be: Why and how do they occur faster or earlier than average? The answer will not be found in the postmortem SDAT brain, because in such a brain, cells are already dead, so not only will those pathways be abnormal, but perhaps all others as well (such as Krebs cycle, electron transport system, cAMP signaling, etc.). Apparently, they are not the initial causes (although targeting them may ameliorate the conditions of the patients). In conventional diseases, we identify the initial causes by simply comparing patients with normal subjects (e.g., in AIDS or pneumonia). But in a chronic disorder such as osteoporosis, such a comparison will reveal numerous "pathogenic errors" in the dying or dead bone cells.

Now, where to find the initial causes in senile osteoporosis or dementia? They must have occurred decades ago, i.e., at a time when the patient was normal. Evidently, such a subject would not display any clear-cut differences compared to truly normal persons. Therefore, we should search for invisible elements that can intensify the aging process into severe consequences only after decade-long actions. Conceptually, such elements are not pathogens, but more likely risk factors.

It should be pointed out that once SDAT is officially defined as a conventional disease (7), it would desperately need a toxin/pathogen to be justified. Under this pressure, the cellular damages, mutant genes, plaques, tangles, or other prominent lesions would have to be considered common pathogens because they fit in with the definition and offer a hope for quick cure.

Q: Your theory would mean that SDAT would be hopeless because we would have no pathogen/error to get hands on. 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" strategy; that is, to preserve or extend the functional lifespan of the brain to match that of other organs, a task quiet 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 be extended as well?

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 and hormones as aging advances. This is also the ultimate reason for the accumulation of plaques, tangles, free radicals, and other age-dependent lesions. Thus, at the present time, replenishing these vital factors is perhaps the most important approach to slowing down neurodegeneration, i.e., doing for the brain just as what we have done to old bones and muscles.

Q: Hormones and growth factors are long known, but they only have very limited effects. How can we place our hope in them?

A: This is mainly 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., estrogen increases the risk of breast cancer).

These shortcomings would call for a revolutionary drug-delivery method that will ensure the brain-specific and extra long-lasting effects of the drugs. In this regard, recent studies have shown, for example, that transplanting cells carrying genes for nerve growth factor into animal brain has slowed down age-related neurodegeneration (14). 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. Such study areas warrant vigorous investigations.

Dementia is due to insufficient synaptic activities, thus ideal drugs for it would be those that can stimulate various neurotransmitter receptors (cholinergic, glutaminergic, and other systems and their subclasses). Alone this line, an intriguing question arises: Maybe such drugs already exist in the mother nature? Perhaps a group of the so-called "psychostimulants" should be of particular interest such as nicotine, caffeine, marijuana, or amphetamine. They specifically excite brain cells thus causing problems in healthy people, but such an action may be exactly what SDAT patients need.

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 (15, 16), 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 will activate oldest-old memories that are associated with basic living abilities.

Such social supports require the participation of society as a whole, thus they should be part of a national awareness program and medical treatments will not be fully successful without them. Such supports will not in and of themselves "cure" senile dementia, but they will help win a few critical years at end-life stages, and thus will largely relieve our social burdens.

In conclusion, society must realize that along with longer life expectancy will come some unprecedented "side effects". Yet, higher cognitive neurons will not be replaced by any technology because they, unlike any other parts of the body and brain, carry the memories. Therefore, our only practical goal is perhaps to preserve or rescue neurons at an unprecedented life stage. To such an unprecedented task, there may not be a quick and simple solution.

Our hypothesis can be summarized in the following two figures:

Fig. 1. An unprecedented demographic change underlies the widespread of SDAT
Aging, not "pathogens", triggers plaque/tangle depositions and neurotransmission (Ntrsn) deficits, and diminishes brain cell vitality (A). But these changes will not lead to dementia unless two additional conditions are met: advanced age (B; note a dramatic increase of this age group today) and risk factors in life (see Fig. 2 below). This model encompasses the current "amyloid hypothesis" (in red color) in two aspects: it further explains (i) where plaques come from; and (ii) why only some elderly develop dementia. Also note dementia prevalence increases exponentially only during advanced aging. Data source, see ref. 3.

Fig. 2. The proposed role of risk factors in senile disorders
As aging progresses into advanced stages, its burdens will dramatically increase to a critical point. Under this condition, various risk factors, which may not be harmful at other life stages, can push cells/organs over the brink. Logically, this model would point to two basic approaches for postponing SDAT: (i) boosting the old cell vitality; and (ii) avoiding risk factors in life.

References:

1. Chen, M., Fernandez, H.L. Where do Alzheimer's plaques and tangles come from? Aging-induced protein degradation inefficiency. Front. Biosci. 6, e1-11 (2001). (Abstract linked to free full-text )

2. Chen, M., Fernandez, H.L. Revisiting Alzheimer's disease from a new perspective: can "risk factors" play a key role? J. Alzheimer Dis. 2, 97-108 (2000). (Abstract )

3. Chen, M., Fernandez, H.L. Alzheimer movement re-examined 25 years later: is it a "disease" or a senile condition in medical nature? Front. Biosci. 6, e30-40 (2001). (Abstract linked to free full-text)

4. Fox, P. From senility to Alzheimer's disease: The rise of the Alzheimer's disease movement. Milbank Q. 67, 58-102 (1989)

5. Gillick, M.R. Tangled minds. Understanding Alzheimer's disease and other dementia. Penquin Group, New York (1998)

6. Von Dras, D.D., Blumenthal, H.T. Dementia of the aged: disease or atypical-accelerated aging? Biopathological and psychological perspectives. J. Am. Geriatr. Soc. 40, 285-294 (1992)

7. Khachaturian, Z.S. Toward a comprehensive theory of Alzheimer's disease--challenges, caveats, and parameters. Ann. N. Y. Acad. Sci. 924, 184-193 (2000). (Abstract )

8. Cassel, C.K., Cohen, H.J., Larson, E.B., Meier, D.E., Resnick, N.M., Rubenstein, L.Z., Sorenson, L.B. (eds) Geriatric Medicine. 3th edn. Springer, New York (1997)

9. Kelley, W.N. et al. (eds) Textbook of Internal Medicine. 2nd edn. J.B. Lippincott Co. Philadelphia (1992)

10. Terry, R.D., and Katzman, R. Life span and synapses: will there be a primary senile dementia? Neurobiol Aging, 22, 347-348 (2001). (Abstract)

11. Scheinberg, P. Alzheimer pathology. Neurol. 43, 1058-1059 (1993)

12. Holliday, R. Ageing in the 21st century. Lancet 354, suppl:SIV4 (1999)

13. Arriagada, P.V., Marzloff, K., Hyman, B.T. Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer's disease. Neurol. 42, 1681-1688 (1992). (Abstract)

14. Smith, D.E., Roberts, J., Gage, F.H., Tuszynski, M.H. Age-associated neuronal atrophy occurs in the primate brain and is reversible by growth factor gene therapy. Proc. Natl. Acad. Sci. USA. 96, 10893-10898 (1999). (Abstract)

15. Fratiglioni, L., Wang, H.X., Ericsson, K., Maytan, M., Winblad, B. Influence of social network on occurrence of dementia: a community-based longitudinal study. Lancet 355, 1315-1319 (2000). (Abstract)

16. Snowdon, D.A. Aging and Alzheimer's disease: lessons from the Nun study. Gerontologist 37, 150-156 (1997).(Abstract)

Comments

While some issues raised in this hypothesis are mind-stimulating, they also imply that AD would be inevitable if we live long enough. This view is against our faith that "AD must be avoidable". All our studies are based on it, otherwise why do AD research? - JD Wong, Ph.D. - Posted 11 March 2002

Reply by Ming Chen: - Posted 24 March 2002

When I say our organs will eventually fail, I talk about a law of nature. This law needs to be emphasized today because only it can explain why everybody's vital organs will fail in the end, and why non-vital organ failures (loss of teeth, hearing, memory, etc.) have affected over 50% of the people by certain age.

However, at the same time I also believe that AD is avoidable in most cases. This is because typical AD cases occur at around age 80 today (Fig. 1, above). In these people, brain failure should, and can, be avoided (because half of the people by age 90 have maintained healthy brains). Evidently, making radios that will outlast the car's lifespan is quite different from making radios that work forever. So you see, it is the mix of the two different concepts that has led to so much confusion in the research community.

Some may say that this goal is too pessimistic because such radios will still fail if the car runs longer. They believe that normal human lifespan should be at least 150 years. Judged by this view, then of course, there would be no such things as "natural death," "senile dementia," or even "successful aging," and any organ failures that occurred today -- no matter at what age -- would be considered bona fide "diseases." Now this view has been vigorously touted by the media and it has inconspicuously changed our starting point of reasoning.

Which goal is a realistic one? What should be the basis we use to define the medical nature of senile disorders today? - Ming Chen

Comment

I agree AD is different from AIDS, but doubt that it is also different from cancer. AD and some cancers may have similar origins because they both are age-related and both due to metabolic inefficiency in late life. If cancer is a discrete disease and aging is a risk factor for it, then why is AD not so? Old cars can also have accidents. - spmacnolin@yahoo.com - Posted 15 April 2002

Reply by Ming Chen: - Posted 8 May 2002

Here is why cancer is conceptually different from AD. While cancer origins are not fully understood, it is known that they involve an error in cell cycle regulation, which diverts normal metabolism into pathological outgrowth. Some cancers, such as prostate and breast cancers, are also age-related and can be attributed to metabolic inefficiency. But in this case, the cell cycle error is primary (i.e. the cause), aging and other risk factors are only helping or are supplementary. Their relationships are much like an old car and bad weather: increasing the chance of accident, but the accident will not occur as long as the driver does not make mistakes. Because a cell cycle error is involved, it governs that the rate of prostate and breast cancers must be low even at their highest-risk age of 80 (actually no more than 5 percent in each case). The rate goes down afterwards, suggesting that aging and risk factors do not play a primary role. Because of the error, there is a decent expectation that someday, cancers will be corrected and cured.

But "senile disorders" (after age 80) are different. Their rate starts to explode at a time when "age-related" cancers are reduced and it continues upward afterwards. Thus, while they both occur with age, "young old age" (before age 80) is different from "old old age" (after 80). Although it was a reasonable guess that a specific error may also exist in late-onset AD, after so many years of exhaustive studies, it has not been found as a common cause. So, while one can still keep looking, there is a need for us to keep an open mind for other explanations. In late-onset sporadic AD, the currently believed "errors" such as plaques, tangles, free radicals, ion imbalance, hormone depletion, energy/mitochondrial inefficiency, or cholesterol exist not only in patients, but in all elderly. Thus, whichever theory you stick to, you will eventually come down to this same question: why and how can a given lesion become more severe in AD patients than in other elderly? I wish that an answer other than "advanced aging and risk factors" could be found.

Risk factors, risk factors, too many risk factors. What's the cause? That's all we want! Well, after pondering this issue over and over again, I now think that senile disorders may not have a "cause" in its common sense (that is, a single pathogen that definitely leads to disease in most patients, like HIV in AIDS). Rather, senile disorders may only have risk factors! That is, they will eventually happen in very old age, but when and how they happen in most people will depend on a whole bunch of factors such as what you do in life, what you eat and what your individual background is. And first of all, how long your vital organs will last (which allows the non-vital organ failures to be seen). Some researchers may not like this view. But wait and see, we may have to revisit it 10 or 20 years from now if the "cause" is still not found.

Your question also raised an important issue, that is, the current term "age-related" diseases. This term does not distinguish the low-prevalence diseases that occur mostly at age 40-70 (i.e., early aging or midlife today), and the high-prevalence diseases after age 80 (which creates a social problem). So it has led to conceptual confusions in research. Here I propose Table 1 below for critique. I think that the former belongs in conventional diseases, but the latter in a different category. Simply put, an old car can have an accident, but that is different from the eventual failure of the car. This way, we would have three types of diseases in terms of their relationships with age, but they belong in two general classes:

Class	Conventional diseases		Senile diseases
Subclass	1. Non age-related	2. Age-related (midlife)	3. Advanced age-dependent
Example	AIDS, polio, Down's, pneumonia, leukemia, hepatitis, prion diseases	Breast/prostate cancers, hypertension, familial AD, ALS (age 40-70)	LOAD, hearing, vision and tooth loss, heart failure, cataracts, muscle atrophy, Parkinson's (after age 80)
Occurrences	Young or any age	Increase with age, then decrease after certain age	Exponentially increase throughout aging; widespread only recently
Role of age	Minor or no effect	Risk-enhancing	Decisive if plus other risk factors
Analogy	Car defect or accident	Old car accident	Eventual failure of very old car
prevalence	Rare or low		High to majority
Origin	Pathogens or metabolic errors		Advanced aging plus risk factors
Treatment strategy	Inhibiting pathogens or correcting errors		Re-activating inefficient metabolisms and avoiding risk factors
Trend	Decrease with medical progress		Increase with longer life expectancy
Study goal	Cure or eliminate		Postpone to a certain extent