Is There Alzheimer’s Disease?

by Peter Whitehouse, MD, PhD on 15 October 2015

Of course there is, but, as the expression goes, “It’s complicated”. Our contention is that Alzheimer’s is more of a disease of minds than a disease of brains. Conceptually, it is two words: an eponym attached to a socially agreed-upon (but contested), medicalized form of memory and other cognitive loss. Alzheimer’s is a frame, a label, a social construct embedded in a certain cultural and historical moment that has imbued it with meaning. To truly examine the question of whether there is Alzheimer’s disease, we must acknowledge that this ‘disease’, as we understand it, has existed for just over 100 years, and will continue to change and evolve over time in human minds. Indeed, over the centuries, the phenomenon of age-related memory loss has been causally associated with witchcraft, moral degeneracy, bad blood, and a dissipation of vital energy from the brain among other factors. It is only in recent human history that we have come to associate the condition with individual brain pathology, and the progressive loss of cognitive function in multiple areas.

Of course, the molecularly inclined would say with great conviction that Alzheimer’s is fundamentally a degenerative dementia, different than aging, and the most common cause of progressive cognitive impairment in the world. This story, which has been the conceptual bedrock of the field for over three decades, has begun to weaken in recent years. Why is this so? We have come to realize the disconnection between various microscopic findings in the brain and the clinical features shown by the patient. Most glaringly, people without cognitive impairment can have plaques and tangles, and persons with “clinical” Alzheimer’s can have an absence of such features. Even people with familial Alzheimer’s disease who carry rare autosomal dominant mutations demonstrate different brain biologies and clinical presentations. In all-too-rare moments of honesty, scientists in the field acknowledge that we know so little about the true nature of plaques and tangles and their related proteins. Yet the fact that these “pathological hallmarks” clearly don’t correlate with dementia does not stop us from making massive investments in trying to cure the disease through various approaches, most of which focus on amyloid immunotherapy. In this way, our conceptualization of “Alzheimer’s” as a disease akin to polio or malaria (with a single pathogen) has proven actively disruptive, and steered us away not only from other pharmacological approaches, but also other public health approaches capable of moving the needle on brain aging (e.g., smoking cessation, improved diets and access to healthy foods, toxic exposures, opportunities for physical activity, etc.).

Moreover, we so often hear that the most common cause of dementia is Alzheimer’s, and our militaristic understanding of plaques and tangles have caused us to view “it” as a singular condition separate from normal aging that “attacks” millions of people around the world. And yet science has established that “Alzheimer’s” is actually a highly heterogeneous set of age-related conditions. Indeed, the most common cause of dementia is “mixed dementia”, which shows a variety of neurodegenerative, vascular, and other components, depending on many genetic and environmental factors that affect individuals in different ways. The fact is Alzheimer’s disease is related to aging, and despite billions of dollars being spent, there is no definitive way to distinguish someone with so-called Alzheimer’s disease from someone with severe brain aging. As such, “Alzheimer’s disease” is much more effective as a political/fundraising slogan than as a proper scientific concept. We would much more appropriately speak of “Alzheimer’s diseases” (plural) or “Alzheimer’s syndrome”.

We sometimes make the light-hearted but serious point that our conceptual dissonance about Alzheimer’s disease has led to increasing “semantic ataxia” as we have “staggered” from one disease category to another. The “discovery” (better labeled as invention) of mild cognitive impairment (MCI) in the last decade was a huge contributor to this confusion. MCI is said to exist in the boundaries between normal aging and disease. Its proponents argue that it can be diagnosed not as a disease, but rather as a condition or a risk factor. Even so, countless people now possess or are possessed by this particular label perhaps not realizing that experts can’t even agree on its definition criteria. Some people with a label may feel they have escaped Alzheimer’s disease or dementia whereas other may learn that it eventually becomes a dementia and be affected by diagnostic creep. Not satisfied with that one label, we have since invented “pre” mild cognitive impairment, “early” mild cognitive impairment, and “late” mild cognitive impairment. All the while, we were very confused about impairments of activities of daily living in these conditions. Were activities of daily living normal or relatively spared?

The process of modifying the nosological construct of “Alzheimer’s disease” has continued with the recent creation of “asymptomatic Alzheimer’s disease” or “preclinical” forms. Now, we are in an era where we use biomarkers (amyloid and tau) that, as mentioned above, may not even be reliable (let alone validated) to label people yet again and potentially medicalize individuals who are not yet clinically affected by cognitive loss. These “pre-disease” terms were originally proposed as research categories, but they are being actively pushed by the Alzheimer’s Association and commercial interests that want to make money out of diagnostic testing using amyloid imaging and eventually sell powerful drugs to people who have no symptoms. Again, the goal posts of Alzheimer’s disease shift with cultural, economic, and political forces. To frame the game as being played on the moral high ground of addressing the suffering of others often avoids the more hidden game in which a privileged group of people who are vested economically or career-wise benefit with fame and fortune.

Indeed, as this “march to progress” on Alzheimer’s continues, immoral, illegal, and irresponsible behavior walk hand-in-hand. Drug companies are fined billions of dollars for illegally promoting off label use of drugs (this apparently being part of their business plan) and doctors seem happy to prescribe them, particularly after a good wining and dining. A recent report from the Alzheimer’s Association claims that billions of dollars more invested into basic research (which itself is having enormous difficulties with fundamental issues like replication of claimed breakthroughs) will lead to effective medications that will save hundreds of billions, if not trillions, of dollars. You know that when they make these projections they imagine that the cost of this magic bullet will be zero [1]. Magic indeed.

Ultimately, because “Alzheimer’s disease” is a socially-constructed disease of the mind and not just a biological disease of the brain, it is about far bigger issues than just Alzheimer’s disease. The Alzheimer’s industry, or “Empire” as we referred to it in our book The Myth of Alzheimer’s [2], has generated enormous fears in aging people by conjuring powerful images of a “death that leaves the body behind”, a “mind-robber”, and a disease that “steals the self” and generates enormous caregiver “burden”. At the societal level, it has summoned up apocalyptic imagery of demographic tidal waves, silver tsunamis, or roving bands of demented zombies to auger an economic collapse that is inevitable without a cure. In our opinion, the Alzheimer’s field has cancer envy. They want the fear, and the money, and the prestige, and the attention that the cancer field gets; yet, they seem unaware of the well-documented concerns in oncology about overselling cure and declaring “war” on cancer. Even the appellation “cancer” itself has been acknowledged as problematic due to the heterogeneity that also is present in Alzheimer’s.

Further, the Alzheimer’s industry says we must “care today and cure tomorrow” as if pharmaceutical treatments will eliminate the need for caring people and communities. This is a critical time to reflect honestly on what we have learned in the last quarter century of research. The primary lesson is that “Alzheimer’s” encompasses many illnesses –it is an umbrella term for many age-related processes that we have fundamentally miscast as a ‘singular disease separate from aging’ to the public. Moreover, we believe that the merging of familial Alzheimer’s disease and sporadic Alzheimer’s disease and the effort to instill a “politics of anguish” around the condition, which was an intentional political move made by the National Institute on Aging in the 1970s to raise funds for an organization responsible for an aging population, may have been a mistake. We have learned that as one grows older, dementia becomes more common to the point we all might be affected if we live long enough. And we have learned that hundreds of billions of dollars invested in medications has led to very little except exaggerated false promises. Perhaps this reflection should lead to a little more humility. After all, aging and the brain and human caring are complex, and, as such, simplistic solutions are likely to be wrong. The past 25 years in the field have been characterized by one promised breakthrough after another to the point we must more honestly stand on the raised heap of these failed breakthroughs and call it a huge breakdown.

Yet we are learning that there are different approaches to responding to brain aging as human communities. The words “Alzheimer’s disease” are largely disappearing in some clinical and policy circles, except perhaps in the United States (and some other wealthier countries) where the false hope of simplistic reductionistic medical approaches remain in force. Elsewhere in the world, people and organizations (such as the World Health Organization and Alzheimer’s Disease International) are focusing more on “dementia” and finally looking to prevention not through vaccinations or promises of absolute cures but rather through public health interventions and collective action on known risk factors. It seems quite clear that attention to diet, exercise, cognitive activity, and social engagement has already reduced the incidence of dementia (as evidenced by falling dementia rates in countries like Sweden, Norway, and the UK) and that there is still much more progress to be made in this area. Again, the notion that “Alzheimer’s” can be a gateway to thinking about larger societal issues that have a bearing on quality of human lives deserves greater attention.

There is hope for human beings as we age with regard to our cognitive vitality. We can create communities where people support one another in better ways. Yes, we need dementia-friendly communities as the global movement associated with this concept rightly suggests. But these communities must be able to address people with cognitive challenges regardless of diagnosis, and the movement toward age-friendly communities must both be sensitive not only to those with cognitive dysfunction but to people of all ages. Global climate change and income inequity are the biggest contemporary challenges that we must address for the health and sustainability of our species. People with dementia are at risk for both ecological and economic disaster. Elders and children particularly share that vulnerability.

So yes, Alzheimer’s disease exists as a human phenomenon that causes suffering and as powerful construct, but its utility as a research and clinical concept is now failing and beginning to transmute. The two words remain a meme in the zeitgeist because the ‘disease’ is associated with a successful strategy to create fear, promise false hope, and gain social resources for those dishonest enough to perpetuate the myth. However, new stories are beginning to win in the public space, and with those new stories can come new values, attitudes, beliefs, and practices aligned with more humane caring for persons with aging bodies and brains, not to mention better science.

Peter J. Whitehouse, Daniel R. George

References
[1] Whitehouse PJ, George DR (2016) Editorial: A tale of two reports: what recent publications from the Alzheimer’s Association and Institute of Medicine say about the state of the field. J Alzheimers Dis, doi: 10.3233/JAD-150663.
[2] http://www.themythofalzheimers.com/

Last comment on 5 February 2016 by J. Wesson Ashford, MD, PhD

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This recent contribution of Whitehouse and George is certainly thought provoking. That is, what could they possibly mean when they say, “ Alzheimer’s is more of a disease of minds than a disease of brains”? The Alzheimer’s disease (AD) patients we have seen have atrophy of the cerebral cortex, loss of dendrites and axons and deposits of abnormally aggregated proteins, in addition to other cerebral pathologies (as described initially by Alois Alzheimer and others over 100 years ago). Can Whitehouse and George deny this? Is this pathology not supremely convincing evidence of a disease of the brain, and not a disease of the mind?

Yes, they are correct, the phrase “Alzheimer’s disease” is a “frame, a label” and a “social construct”. But this is also true of “malignant melanoma”, “multiple sclerosis”, “smallpox” and others. Such “frames” are needed! The labeling involved in the use of these frames is valuable and necessary since categorization of a disease with a name helps patients, caregivers, medical professional, public health workers and government officials to deal with the illness. Sadly, the US Alzheimer Association has reported that only 45% of AD patients are told their diagnosis [1]. This leads to frustration and unnecessary visits to physicians in search of a diagnosis.

Of course it is only in recent history that we have come to refer to marked age-related memory loss as a disease, even though it previously had other religious or mystical explanations. The same can be said of epilepsy and countless other conditions. And of course our knowledge about plaques and tangles is not complete and great gaps still need to be filled. And yes, we should pay attention to smoking cessation, diet, physical activity, toxic exposures and other risk factors [2]. Research on the pathophysiology of the disease itself does NOT deter anyone from pursuing health measures on an individual or public basis! Moreover, calling a disease by a single name doesn't mean that it has a single pathogen. (Malaria, proposed by Whitehouse and George as a disease with a single pathogen, actually has over 4 main causes). Yes, AD is heterogeneous. This has been known for many years [3]. But so is epilepsy and multiple sclerosis: even though these conditions are heterogeneous the names remain useful concepts.

The authors are also misleading us concerning the relationships of age to memory loss. Many studies show that a substantial proportion of centenarians are not demented [4]. It is absurd to propose, “Dementia becomes more common to the point we all might be affected if we live long enough”. This is equivalent to asking what kind of music Johann Sebastian Bach would write if he were alive today! And I am not willing to tell one of my many AD patients in their 50s that they suffer from an “aging brain”.

The implications of making the claim that AD doesn’t exist are also worrying. It threatens to unravel the decades of effort put in by organizations such as Alzheimer Disease International to legitimize the disease in member countries so that proper diagnosis and care can be made available. And we have to also acknowledge an obligation towards the efforts of scores of persons with the disease who have overcome their fear and anxiety to come forward to speak out. Legitimizing AD as a disease also helped bring about the deinstitutionalization of dementia care in Japan where dementia was previously thought to be a disease of the mind with patients locked up in psychiatric hospitals. Recognition of AD as disease of the brain has helped to foster the progress of small-scale residential care such as group homes in Japan, which are covered under their Long Term Care Insurance.

We agree that more efforts should be focused on the proper care of persons with dementia; but to demote the status of the disease to a “disease of the mind’ will damage those suffering with the disease and their families. Affected persons must have access to healthcare resources. Insurance coverage for mental disorders has always been less that that for other conditions.

Finally, Whitehouse and George denigrate the concept of an Alzheimer cure. Perhaps they have mystical abilities, which most of us lack, to predict the future. We must remember polio! (28,985 cases in the USA in 1955, the year the vaccine was introduced, and 61 cases in 1965 [5]. We must have the courage and imagination to pursue a diverse research agenda.

Yes, we do need humane caring for persons with AD. We also need the courage to address the mechanisms that are responsible for the initiation and maintenance of AD pathology in both sporadic and familial cases. To throw out the last hundred years of progress in this field through pretentious jargon is supremely unwise as well as irresponsible.

Robert P. Friedland, MD, and Shivani Nandi, PhD

References
[1] Alzheimer's Disease Facts and Figures, Alzheimer Association, 2105.
[2] Friedland RP, Nandi S (2013) A modest proposal for a longitudinal study of dementia prevention (with apologies to Jonathan Swift, 1729). J Alzheimers Dis 33, 313-315.
[3] Friedland RP, Koss E, Haxby JV, Grady CL, Luxenberg J, Schapiro MB, Kaye J (1988) NIH conference. Alzheimer disease: clinical and biological heterogeneity. Ann Intern Med. 109, 298-311.
[4] Poon LW, Woodard JL, Stephen Miller L, Green R, Gearing M, Davey A, Arnold J, Martin P, Siegler IC, Nahapetyan L, Kim YS, Markesbery W (2012) Understanding dementia prevalence among centenarians. J Gerontol A Biol Sci Med Sci 67, 358-365.
[5] Centers for Disease Control and Prevention. http://www.cdc.gov/vaccines/vpd-vac/polio/dis-faqs.htm

We thank our former colleagues Drs. Friedland and Nandi for taking the time to respond so passionately to what they kindly referred to as our “thought-provoking” piece. They restate many of the standard criticisms of our position, and we refer the reader to our website for more adequate information to address their concerns (www.themythofalzheimers.com).

Let’s start with what we do agree about. All diagnostic labels are frames, or social constructions, and, as they organize the way humans understand and behave towards illness, they are important and powerful. We also agree that all diseases are, to one degree or another, heterogeneous and multi-causal (although the degree to which diseases exhibit heterogeneity is of course highly variable). Age-related memory problems are common and will be an increasing concern as our world ages. Similar phenomena can occur in younger people, but whether we lump the often more strongly genetic early forms with late-life types of so-called “Alzheimer’s disease” together remains uncertain. We also support basic research into the biology of “Alzheimer’s” and aging, but are concerned about the balance of priorities in a world driven far too much by pharmaceutical thinking and values. We also agree that good has come from bringing the problem of dementia to public and policymaker attention, but we think this has been done with too strong a medical/molecular agenda that has too frequently gone unquestioned. We also agree that no one can predict the future exactly, but current trends about aging demographics, income inequity, and global climate change are reasonable to include in one’s thinking about the future and how to act in the present. Lastly, we agree that our research agenda should be diversified – a reality demanded by the heterogeneity, age-related, and multi-factorial nature of “AD”.  

Where do we disagree?  We are tired of hearing the polio analogies that so often fuel the “march to progress” rhetoric used by our colleagues. Yes, the public health campaign against polio was a remarkable success, but whatever “Alzheimer’s disease” is, it doesn’t appear to be an illness resembling polio. Success in one medical area does not imply that success will occur in another. We are also weary of hearing about the “clear-cut pathology” associated with Alzheimer’s. As Dr. Alois Alzheimer himself realized in just the first two cases he studied in the early 20th-century, the pathology of “AD” is not clear and has become increasingly muddied as we learn more about plaques and tangles. The biology overlaps with aging, and most older people have a mixed dementia and not just “pure Alzheimer’s” (i.e. just plaques and tangles). Further, we are less certain about the value of very early diagnosis, particularly “presymptomatic Alzheimer’s disease” based largely on validated and costly biomarkers. But what about mild cognitive impairment? Do people who propose early diagnosis need to go out and expose people to this variably defined and unclear term, especially when memory loss is so stigmatized in Western culture?

 

In our view, it is time to be a bit more reflective and honest about what we know and what we do not about age-related memory problems, and to abandon an often self-serving professional stance that we are always on the “march to progress”. It is a time for a further shift towards public health and social models, imbued with the creativity of the arts, which can guide us in humanely addressing these very real challenges. 

 

Three examples of people who shared their experience with me this week. A daughter telling me that her mother with dementia becomes more and more suspicious towards her husband who cares for her. She accuses him of stealing her money, betraying him with other women and working for the mafia. The daughter has to make long phone calls to calm her down and this is going on for months now. A family member of me whose husband has Alzheimer’s disease wrote that he fell out of the bed in the middle of the night on his face. There was blood everywhere. When she asked what happened he said: “I was hit by a car”. And a man caring for his mother in a developing country while he has a job as well, urgently seeking support and advice.

Is this all caused by a disease that disappears when we change our mind-set, as Peter and Danny are arguing in this article? No, it is a disease of the brain and it hits millions of people in their day to day lives every day. They need help now and hope for the future. An academic discussion like this is not adding any benefits to their situation. Peter Whitehouse is telling this story now for 8 or 9 years, but it has not brought us any further. Some people learn from their mistakes. Apparently he doesn’t.

Peter and Danny: can you stop stabbing me in the back? Alzheimer’s Disease International (ADI) is tirelessly working on getting better care and support for people with dementia and their families, and so our hundreds of staff and thousands of volunteers of Alzheimer associations around the world. More and more governments recognise the problem but hesitate to act, afraid of the cost of improving their health systems. You give them an easy excuse: just changing our minds would make the problem disappear. I call this irresponsible behaviour. With your knowledge and talent you can do so much better. For instance by convincing the US government that anti-smoking campaigns should include messages about brain damage as well. Or produce research evidence on the effectiveness of care interventions that you say are important. Those would be useful contributions to solving this issue.

Thank you,

Marc Wortmann, Executive Director, Alzheimer’s Disease International

Dear Mark,

Let’s begin with what we agree about. Age-associated cognitive impairment is a real, huge,  and growing problem, and personal, familial, and community suffering can be awful. However, humans are not just biologic entities; rather, we are meaning-making creatures. Therefore, words and especially diagnostic labels are undeniably powerful, and the meanings we choose to associate with diseases and illnesses have the effect of positioning and delimiting people within our societies. Stories are a good way to make an impact because they humanize the people beneath the labels and bring forth richer meanings. You start with stories and we will too.

Volunteers with memory loss in our Intergenerational School in Cleveland (www.tisonline.org) have a meaningful purpose in our community. Take Mrs. Barbara Kelsey, who was our volunteer of the year in 2009. As she waited to be recognized at our annual banquet she leaned over to her caregiver to ask why she was there, and her caregiver reminded her that she had volunteered to read with children each week of the school year. In fact, in 2009, your organization Alzheimer’s  Disease International honored the school with an award for our research demonstrating tangible biopsychosocial improvements of intergenerational volunteering for people with dementia. Each year, dozens of people like Mrs. Kelsey are invited to volunteer in the school. Here, their mental illness labels (“dementia”, “Alzheimer’s”, “Frontal-lobe dementia”, etc.) disappear in the context of relationships with school children who meet them in the moment and honor their remaining strengths instead of dwelling on their deficits, as the disease-centric models cause us to do.

We are spreading this message of humane, community-based care through Intergenerational Schools International with funding to start programs in Spain and India. In fact, I (Peter) am writing this from the American Public Health Association in Chicago where as a member of the Governing Council I am working on policies on dementia and spreading the word about prevention and brain health. I have leadership and advocacy roles in a variety of organizations in Washington including the National Center for Creative Aging, AARP, and Dementia Friendly Communities initiative etc. Please do not tell me I am resting on an old story. I am helping birth a new more balanced message about how we need to address these challenges globally.

Here in Chicago I walk by a skyscraper with the message #EndAlz presumably produced by a member organization of your group that issues reports saying how we can save trillions of dollars if we just develop a magic drug by 2015 that they model as being “free”. Let’s be careful about what we call “irresponsible” and what constitutes responsible innovation. Drug companies and their friends lie and distort our very conceptions of what it means to be healthy. We need to look for institutional corruption wherever we find it in our field rather than attacking those who are challenging our current disease-models and sharing a more humane vision.

I am saddened that after our many chats all around the world you distort our message so fundamentally. Memory loss and the phenomenology of dementia are real; but “Alzheimer’s” is not one disease so different from aging that it can be cured if we just spend enough money on it. You told me once that people need to have hope through seeking a cure. I am not talking about disinvesting in all research; rather, I am talking about investing in a better-balanced approach. Sometimes I think ADI is about that too. And if we do that and develop better brain health preventatives and age/dementia-friendly communities we will all benefit, including children, not just elders.

 

I have learned a lot in my decades of work subsequent to discovering brain pathologies and helping to develop the first generation drugs in the 1980s – but I do not think the field has learned enough. ADI could provide some real leadership here.  What have you learned? 

It has become more and more clear that there has been a total failure of development of therapies for Alzheimer’s disease (AD) [1-4]. Even the FDA approved medications, while making billions of dollars for drug companies and possibly contributing some cost-effective benefit such as delaying nursing-home placement, do not stop the relentless progression of AD. As many organizations have widely publicized, with the graying of the population and the progressive extension of longevity [5], the problem of dementia, and AD in particular, will have a very negative impact on society. And, on top of that, dementia leads to the waste of a mind and nobody wants to get into that state.

So, with the looming crisis and the failure of our quasi-scientific society (anyone who thinks that our world is ideal and not based on competition and survival of the fittest is hopelessly naïve) to solve the dementia problem, it is understandable that there is great frustration in the field of dementia and AD. Dr. Whitehouse is clearly expressing his frustration with this field, in which he was an early pioneer. But, there is an important analysis needed of his “blog” statement, to separate what represents Dr. Whitehouse’s appropriate frustrations from misleading statements that have been made due to this frustration. It is also important to dissect where Dr. Whitehouse’s knowledge of the field has led to legitimate criticism versus other points which appear to represent his lack of knowledge or misunderstanding of many critical aspects of dementia and AD. Unfortunately, many of Dr. Whitehouse’s statements appear to be general complaints about reality and anti-establishment rhetoric (reminiscent of the 60s), filled with unscientific bias, nihilistic and cynical, which are not constructive. Other commentaries have already attempted to correct Dr. Whitehouse’s misleading statements, with little effect on his overall disposition.

Neuropathological definition of a disease is a fundamental issue. Alzheimer’s disease has been clearly defined as a neuropathological entity, and study of a variety of pathological approaches supports this view [6]. The incidence of dementia and Alzheimer’s disease appear to double every 5 years [7]. This finding indicates that dementia and Alzheimer’s disease are conditions which have an even closer relationship with the fundamental Gompertzian kinetics of aging than many other common diseases [8]. The basic, unfortunate problem is that as we age, the number of biological failures which our body experiences increases exponentially, and the dynamics of this problem are related to the evolution of our species into an ancient ecological niche. What is most remarkable has been the appearance of the apolipoprotein (APOE) e-3 and e2 alleles (300,000 and 200,000 years ago respectively), to displace the e4-allele by more than 85% [9]. Since the ancient APOE e4 allele is highly associated with Alzheimer’s disease [10], it is fortunate that evolution in modern times has been so active in presumably greatly decreasing what could have been a much greater incidence of Alzheimer’s disease if the e3 and e2 alleles had not appeared and propagated. The experience that homozygous e2 individuals probably never get Alzheimer’s disease, in spite of their extended longevity, suggests that understanding the role of APOE could lead to complete prevention of AD.

Another fundamental point is that AD is a progressive condition, progressing over time, leading to progressively more and more failure of brain memory mechanisms, thus also following a survival curve which starts very slowly, but gains momentum as the disease progresses [11, 12], affecting cognitive and functional abilities proportionally [13]. The progressively better understanding of the progression of cognitive deterioration associated with AD pathology is important for understanding the condition and considering approaches to its control. It is also important to realize that as aging increases, there are likely to be more and more neurodegenerative conditions in an individual, making diagnosis increasing complex, particularly without the usually avoided autopsy. Further, diet, exercise, and other good health practices may slightly delay the functional manifestations of neurodegenerative disease and greatly decrease cerebrovascular disease, which is likely responsible for the decrease in the incidence of dementia recently detected.

Dr. Whitehouse does join a growing number of voices speaking against the “Amyloid Hypothesis”. There are already many papers castigating this failed view of Alzheimer’s disease. However, the issue is not to throw out the data but to reexamine the data and the conclusions drawn from it. I believe that there is an old hypothesis, the Neuroplasticity Hypothesis of Alzheimer’s disease, which provides a much better explanation for how the AD pathology affects memory and causes dementia [1]. An appropriate understanding of AD and its basic pathophysiology is still our best hope to understand AD and develop a means to prevent it.

At this time, I believe that it is more important to educate the world population about dementia and AD than to confuse them with paranoid propaganda. I have written extensively about the need to screen for cognitive impairment, dementia, and AD [12, 14, 15]. Further, I have worked to develop an easy approach to assessing memory function [16] that can be used around the world over the internet (http://www.memtrax.com). Individuals have generally been reluctant to present to a clinician with a memory problem, but assessing one’s own memory privately and receiving appropriate recommendations for evaluations that could greatly improve their lives should be considered worthwhile. Though a few groups have been against cognitive screening, Congress has mandated cognitive assessment as part of the Medicare Annual Wellness Visit. The issue is not to label people but to assist them to adjust their lives to be as healthy as possible. But, the impact of healthy living, including exercise, provides but a very few years of effect on the development of dementia and AD, small compared to the decades of genetic effects. There is already enough concern about genetic information which itself has substantially hampered the advances in AD as well as other conditions. The world population would do better to become better educated about important conditions than simply blame them on social realities. In fact, it is education which is really needed to protect mankind from most of the social ills described by Dr. Whitehouse.

There are numerous anti-capitalistic statements that Dr. Whitehouse makes which really have no place in an academic discussion. (Since Dr. Whitehouse lives in Cleveland, before he discusses global climate change further, he should learn about the dominant 100,000-year glacial cycles of the large ice sheets in the Northern Hemisphere.) There are basic social problems in the world and the development of inequality has been well documented back to the earliest times. But, the failure to prevent AD should not be blamed on capitalism or even the scientists who narrow-mindedly saw the Amyloid Hypothesis as the path to Alzheimer prevention – initially it was really a very good idea with great mouse data supporting it. However, at this time, there is really a need to focus on early recognition of dementia-related dysfunction and accurate diagnosis to optimize the lives of the afflicted individuals and to broaden the clinical and genetic database to support new scientific endeavors to understand and prevent AD. I believe that reconsidering the Neuroplasticity Hypothesis of AD is the best path to a better future [1].

REFERENCES
[1] Ashford JW (2015) Treatment of Alzheimer’s disease: The legacy of the cholinergic hypothesis, neuroplasticity, and future directions. J Alzheimers Dis 47, 149-156.
[2] Becker RE, Greig NH, Giacobini E, Schneider LS, Ferrucci L (2014) A new roadmap for drug development for Alzheimer's disease. Nat Rev Drug Discov 13, 156.
[3] Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, Mantua V, Mecocci P, Pani L, Winblad B, Kivipelto M (2014) Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014. J Intern Med 275, 251-283.
[4] Gauthier S, Albert M, Fox N, Goedert M, Kivipelto M, Mestre-Ferrandiz J, Middleton LT (2016) Why has therapy development for dementia failed in the last two decades? Alzheimers Dement 12, 60-64.
[5] Oeppen J, Vaupel JW (2002) Demography. Broken limits to life expectancy. Science 296, 1029-1031.
[6] Geddes JW, Tekirian TL, Soultanian NS, Ashford JW, Davis DG, Markesbery WR (1997) Comparison of neuropathologic criteria for the diagnosis of Alzheimer's disease. Neurobiol Aging 18, S99-105.
[7] Jorm AF, Jolley D (1998) The incidence of dementia: a meta-analysis. Neurology 51, 728-733.
[8] Ashford JW, Atwood CS, Blass JP, Bowen RL, Finch CE, Iqbal K, Joseph JA, Perry G (2005) What is aging? What is its role in Alzheimer's disease? What can we do about it? J Alzheimers Dis 7, 247-253; discussion 255-262.
[9] Ashford JW (2004) APOE genotype effects on Alzheimer's disease onset and epidemiology. J Mol Neurosci 23, 157-165.
[10] Raber J, Huang Y, Ashford JW (2004) ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol Aging 25, 641-650.
[11] Ashford JW, Schmitt FA (2001) Modeling the time-course of Alzheimer dementia. Curr Psychiatry Rep 3, 20-28.
[12] Ashford JW (2008) Screening for memory disorder, dementia, and Alzheimer's disease. Aging Health 4, 399-432.
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