Alzheimer's disease (AD) is one of a number of forms of dementia. According to the commonly used definition, dementia requires an irreversible, global impairment of cognitive skills including memory. The impairment must be great enough to interfere with the activities of daily living (1). Common characteristics of dementia include severe memory loss, inability to formulate abstract thoughts, confusion, problems with concentrating, difficulty carrying out both routine and complex tasks, personality changes and paranoid or bizarre behavior (2). These characteristics are the result of abnormal brain processes, not age. Up until about 1975 the term Alzheimer's disease or Alzheimer's dementia was reserved for the rare, early onset (40-60 years old) cases of cognitive loss, now known to generally result from a strong genetic predisposition. In fact, the demented patient cared for by Alois Alzheimer in 1901 in Germany was only 51, died in 1905, and the pathology exhibited by her brain was subsequently described and termed "Alzheimer's disease." Beyond the age of 65 loss of cognitive ability was traditionally viewed as a more or less inevitable consequence of aging (1). When it was recognized that presenile and many senile dementias shared a common pathology, dementias in later life finally became a recognized "disease." While conventional wisdom held that problems caused by normal aging were unavoidable, a true disease theoretically should be subject to both treatment and prevention. This had the highly significant consequence of opening the door for research funding (3). Considering AD as a disease had and still has strong political implications, and in the last decade there has been a virtual explosion in both fundamental and clinical research.

Harrison's Manual of Medicine, 15th Edition, lists five common causes of dementia and nine additional causes among adults. Thus the physician, when confronted with a patient presenting with signs of dementia, clearly faces a daunting task of differential diagnosis, made especially critical since some causes of dementia are treatable and even curable. It is in fact easy to argue that sooner rather than later specialized assessment from a neurologist or a specialist in neuropsychiatry, or both, is highly desirable, not only to avoid the calamity of leaving untreated a curable mental disease but also to identify as early as possible the cause of the dementia in order that therapeutic and delaying tactics can be initiated, even if the underlying disease is in fact judged incurable. A complete medical work-up is also needed to rule out potentially treatable causes of dementia such as encephalopathy, intracranial mass (e.g. tumor), infections that cause dementia, endocrine problems such as an under active thyroid, over-medication, metabolic problems, etc. Depression and delirium can mimic dementia, and are also treatable (2).

AD and vascular dementia (VaD) and a mixture of the two (mixed dementia) appear to be the most common forms, and this review will be restricted to these. The prevalence of dementia in community dwelling individuals over the age of 65 is estimated to be from 6-8%, whereas for those in nursing homes and chronic care facilities, the number can be as high as 75%. Prevalence of AD doubles approximately every 5 years after age 60. It is estimated that at least 30% of the US population over 85 has AD. While disease progression can be delayed, and in a few cases to be discussed below, dramatic reversals have been achieved, the normal course is a steady decline in almost all aspects associated with the "quality of life." For example, the inability to find the way home may be followed by the inability to fine some room in a home occupied for, perhaps, decades. At this stage there are frequently serious disruptive psychological problems as the individual understandably fails to cope with the disability. Resultant behavioral problems may require aggressive intervention with behavior modifying drugs in order for the individual to continue to live at home. Profound depression is also very common. Eventually there is the loss of control of bodily functions, especially urinary control, the loss of the ability to recognize family members, and finally total incapacitation. The average time from diagnosis of AD to death depends on age. Researchers from Johns Hopkins University found that patients diagnosed with AD in their 60s or 70s have a median remaining lifespan of 7- 10 years, whereas those diagnosed in their 90s have a median remaining lifespan of only approximately 3 years (4). Studies suggest that dementia is an underlying but not necessarily primary cause of death. In fact, some studies find that the immediate causes of death are similar in demented and non-demented hospitalized elderly (5). However, individuals with VaD have an increased risk of death due to cardiovascular disease and in particular heart failure when compared to patients with AD (5).

It is common for individuals to seek out professional advice before the symptoms of AD or dementia are present. Generally the complaint relates to memory problems that have become bothersome or have caused as spouse or family member to suggest evaluation. This is covered below under the heading "Mild Cognitive Impairment."

The term Alzheimer's disease, while widely used, has a number of different connotations and modern usage has attempted to clarify the exact meaning. Thus today it is common to see the following definitions (6):

• Definite AD. Presence of clinical characteristics of AD confirmed by histopathological evidence, generally from postmortem study of brain tissue. In the simplest terms, a diagnosis of definite AD requires the patient to already be dead! This state of affairs underlines the difficulty of a definite diagnosis based only on clinical observations (when one is alive). The pathological features that constitute the so- called hall-marks of AD are senile plaques and neurofibrillary tangles, two distinctive formations in brain tissue. Finding them in large numbers at postmortem is taken by most pathologists as proof of AD. Finding them in profusion in the brains of totally non-demented individuals is another matter, and one which illustrates the complexity of this disease.
• Probable AD. Diagnosis is established by clinical examination and an evaluation of mental status via a history and tests. Probable AD is generally defined as requiring deficits in two or more areas of cognition. Dementia must be present. There should be progressive worsening of memory and other cognitive functions. Systemic or other brain diseases that also produce dementia should be ruled out. Normally, the age of onset is between 40 and 90. AD at a young age usually implies a strong genetic or family connection, since in the general population AD is rare prior to about age 60.

Because the neuropathological or histopathological manifestations of AD can occur without producing dementia, it has been suggested (1) that the terms "Alzheimer's disease" and "Alzheimer's dementia" should be used, the former referring to the presence of the neuropathologic characteristics and the latter requiring both the neuropathology and dementia. Both terms obviously require post mortem evidence.

Criteria for vascular dementia are also categorized by "definite" and "probable" as follows (6):

• Definite VaD. Clinical criteria for probable VaD. Autopsy demonstration of appropriate ischemic or hemorrhagic (bleeding) brain injury. No other causes of dementia.
• Probable VaD. Based on clinical evaluation. Decline in cognitive functioning. Deficits severe enough to interfere with the activities of daily living. Absence of any other disorder capable of producing dementia is required. VaD can be related to the effects of a stroke, and a diagnostic factor is neuroimaging evidence of extensive vascular lesions.

It should be noted that neuroimaging (MRI, PET, or single photon emission CT) is becoming a particular valuable tool for the differential diagnosis of dementia (7, 8). Clinical features also allow to some extent the differentiation of VaD and AD (6). VaD can evolve in a stepwise fashion following transient ischemic attacks that are really mini-strokes. They may be accompanied by various frequently vague and transitory symptoms such as light-headedness, dizziness, visual disturbance, headache, or mild tingling of the extremities (9). Also, the development of atherosclerosis over many years can slowly decrease the blood supply to the brain with associated cell damage and cell death due to oxygen and glucose deprivation, resulting eventually in VaD. The dementia can also occur after a sudden, paralyzing stroke. In some cases, post-stroke dementia can be prevented by appropriate treatment (9)

As the population age distribution shifts to older individuals, it is clear that a huge personal and financial burden is looming. While there is a high level of interest among the general public regarding the results and promise of anti-aging research, life extension will be a mixed blessing unless the problem of dementia is solved. It has been estimated that AD afflicts about 15 million people worldwide with about 4 million in the US alone (10). In the absence of a cure or a successful preventative protocol, it is estimated that 14 million Americans will develop AD by 2050 (11). It thus comes as no surprise that one of the most active areas of medical research today, both from the clinical and basic science perspective, involves finding the causes and devising treatments for AD. A literature search using the key word "Alzheimer" brings up about 3000 medical journal references just for the year 2002!

WHAT IS THE CAUSE OF ALZHEIMER'S DISEASE?

The short answer is that nobody really knows for sure. A more detailed answer depends on not only what is meant by the word cause but also how one separates suspected primary causes from effects that by default tend to be viewed as causes. For example, epidemiologic studies (12, 13) suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the incidence of AD in some populations. Can one conclude from this that inflammation actually causes AD? Perhaps inflammation simply contributes to or aggravates some more fundamental causative process. So-called plaques and tangles, the pathological hallmarks of AD, are frequently referred to as the "causes" of AD, but what causes the plaques and tangles? And how does one explain patients totally free of dementia whose brains exhibit large numbers of plaques and tangles? These problems are swept under the rug in some discussions of AD and its etiology, but careful reading of the literature will reveal a number of scientists and clinicians who raise serious questions regarding the conventional wisdom and endeavor to encourage a view which recognizes the multi-factorial nature of the disease.

The conventional wisdom regarding the cause of AD focuses on what is termed the Amyloid Cascade Hypothesis (ACH). In this model, something goes wrong with the metabolism associated with so-called amyloid precursor protein (APP), and the fragments derived from it. These fragments, called amyloid beta or Aß for short, then exhibit an abnormal tendency to aggregate yielding the so-called senile plaques that are seen in AD brains at autopsy. At the same time, something goes wrong with another protein called tau, which leads to the neurofibrillary tangles also seen in the AD brain.

The neuron looks something like an octopus with branches (dendrites) protruding from the central body, one of which, called the axon, is much longer than the others. The axon makes contact and communicates with other neurons through contact (synapses) to the dendrite of another neuron. The AD tangles form in the axon, blocking the flow of nutrients to the nerve endings and interrupting communications inside the cell and eventually killing it. The amyloid plaque that forms at the axon-dendrite contact points inhibits communication and induces an inflammatory reaction, and eventually killing healthy synapses and cells around the plaque. Thus the ACH regards Aß and the plaques as neurotoxic and responsible in part for the death of neurons and the loss of cognitive ability. In the earliest clinical phase, AD is characterized by an almost pure memory impairment, which is thought to be due to synaptic dysfunction caused by Aß (14). What actually triggers these problems with APP, Aß and tau does not seem very clear, nor is there proof that these plaques and tangles directly cause the clinical symptoms of the disease. There appears to be general agreement however, that the dementia is due to the cumulative effect of the death of neurons and the failure of signaling pathways. Some believe that oxidative stress produced by an excess of highly reactive free radicals may play a role in the initiation process. Other theories view inflammation as a trigger or factor, and as well, restricted cerebral blood flow is a frequently cited causative factor. Toxins are also implicated. There are those who believe that both neurotoxicity and neuroprotective process are at work with tau and Aß, and that Aß may actually be neuroprotective in some of its forms and at some stage in it production (15).

The ACH has led to potential therapies. A vaccine for Aß which causes the break-up of senile plaques and the clearance of Aß in mice has been developed by a pharmaceutical company. Human trials were recently halted due to the incidence of a serious inflammatory disorder of the central nervous system observed in a few participants in the trial, a halt that came before any changes in clinical symptoms could be evaluated with statistical significance. If the vaccine had reduced the plaque burden and resulted in clinical improvement, this would have gone a long way toward establishing the merits of the ACH. But this is not to be, at least in the foreseeable future. Pharmaceutical companies are also working on inhibitors for the enzymes that chop off the Aß fragments from the APP, but nobody knows what the overall effects of this type of inhibition might be, since these enzymes have other actions in human biochemistry. The Amyloid Cascade Hypothesis has had a big impact on the direction of therapeutic research, in fact it has dominated it. If the hypothesis is flawed or seriously incomplete, as some think, then considerable time and vast sums of money have been spent, both in academic and pharmaceutical settings, going down only one road, so to speak, at the expense of considering and developing therapeutic alternatives not based on the ACH.

In the view of some neuroscientists the causes and the mechanism of progression of AD are much more complex than is implied by the Amyloid Cascade Hypothesis. Considerable attention is now focused on the significance of the large variety of vascular abnormalities that are also frequently present in the AD brain. In addition, there is the fundamental question of the relationship between the ultimate causes of AD and the many types of cerebral vascular disease. In fact, it has been recognized for some time that AD and vascular disease share many epidemiologic risk factors (16, 17). In a paper recently published in the journal Stroke, de la Torre (18) provides an interesting list of reported risk factors for AD from epidemiologic studies on elderly subjects. Included are atherosclerosis, stroke, diabetes, smoking, high cholesterol, cardiac disease, high serum viscosity, thrombogenic factors, high serum homocysteine, hypertension and hypotension, high fibrinogen levels, and transient ischemic attacks, all of which point to the involvement of vascular disorders. His thesis is that AD, when not caused by a strong genetic predisposition (the early onset type of AD), is initiated by vascular factors that precede the neurodegenerative process. This conclusion he claims is consistent with most of the basic and clinicopathologic data reported for AD, and is not inconsistent with other findings which indicate neurodegenerative processes as the cause of this disorder (18, 19). It has in fact been proposed recently that VaD is the most common form of dementia in the elderly (20), but some studies do not find this to be the case. A detailed discussion of vascular risk factors for AD from an epidemiologic perspective can also be found in a recent review by Breteler (21).

While clinical diagnostic protocols attempt to differentiate AD and VaD (6), and pure AD requires by definition the absence of vascular disease deemed serious enough to cause dementia, it seems clear (17) that in fact not only do AD and VaD share many of the same clinical signs and symptoms, but that the pure forms may represent two extremes of a continuum of pathology. If one looks at the prevalence of common pathological lesions in AD and VaD, many are frequently seen together at significant levels of incidence. Studies suggesting that the biochemistry that leads to plaque formation can be induced in part by vascular disease further justifies the continuum notion by extending it to factors that may be closely related to the ultimate causes (18, 19). de La Torre (22) actually would like to see AD classified as a vascular disorder. He considers that this would likely improve the chances of finding useful treatments because clinical studies could focus on more realistic and relevant pathologic targets than at present.

A recent article in The New England Journal of Medicine (23) underscores the connection between vascular disease and dementia. The study deals with the risk of dementia and cognitive decline associated with so-called silent brain infarcts, which in this context were mini-strokes that went unnoticed by the individual. The effects were seen with MRI imaging, identified if present at baseline, and followed for a number of years with repeated imaging. Neuropsychological assessment was used to establish the presence of dementia and cognitive decline. A significant finding was that silent brain infarcts increased not only the risk of dementia, but also that in this study the majority of cases that occurred were of the Alzheimer subtype. In an accompanying editorial in the same issue, Blass and Ratan point out that such studies provide guidance in intervention because recommendations can be based on the large body of well documented evidence concerning the prevention of vascular disease (24).

Further evidence for the view that the pathological basis for AD has many unresolved issues was recently presented by Vagnucci and Li in the journal Lancet (13). They present a fascinating table that summarizes the relative risk reduction of AD found in high-risk populations resulting from the use of a number of different drugs, including NSAIDs, steroids, histamine H2 blockers (such as Pepcid AC, or Zantac), calcium channel blockers, and lipid lowering agents (statins). Relative risk reductions as low as 0.14 were found for H2 blockers, with most relative risk numbers well below 0.5. These are impressive risk reductions by any standard, and yet the drugs obviously had quite different primary actions, as defined by the indications normally calling for their use (abnormal blood lipid profile, hypertension, heart burn, inflammation from arthritis, etc.). Vagnucci and Li suggest that the connecting factor for the action of this set of drugs, while not excluding other actions, is antiangiogenic activity (inhibition of neovascularization). In their view, AD in part involves the activation of large populations of endothelial cells by angiogenesis due to inflammation and oxygen deprivation. These cells are thought to be involved in the secretion of precursor substrate for Aß and a neurotoxic peptide that selectively kills neurons. They advance the hypothesis that the drugs listed above have antiangiogenesis actions which inhibit this mechanism of neurotoxicity. Considerable evidence is presented for this hypothesis, which may eventually stimulate drug design and clinical trials. The point, however, is how little is really know about the details of what appear to be the highly complex pathological phenomena that ultimately cause AD.

MILD COGNITIVE IMPAIRMENT—AN EARLY WARNING SIGNAL?

Historically, forgetfulness among the elderly was simply considered a normal consequence of aging. Various descriptive, pseudo-medical terms were used (25), including benign senescent forgetfulness, age-associated memory impairment, late-life forgetfulness, etc. However, it has always been possible to find examples of individuals in their 90s or even over a hundred who were most certainly not demented, had little if any cognitive or memory decline, and who were capable of independent living, balancing their checkbook, playing cards, etc. It is interesting that these fortunate individuals were frequently devoid of coexisting disorders, such as diabetes, hypertension, coronary artery disease and sensory abnormalities, any or all of which might accompany "typical" aging (26). Today the term Mild Cognitive Impairment (MCI) is frequently used to describe serious memory problems.

There are a number of causes of (MCI) other than a pre-Alzheimer disorder. These include depression, mini-strokes, alcoholism, vitamin deficiency, low thyroid levels, overmedication, and sleep problems (27). According to Dr. Majid Fotuhi of Harvard Medical School, the majority of people who have memory problems and fear that they have AD may be experiencing the symptoms of depression and are in fact surprised to learn that depression can be viewed as a brain disease (27). Depression is treatable and patients can regain both their memory and a good outlook on life. Just as in the case of AD, it is critical to exclude these other causes of MCI when evaluating a patient with a memory complaint.

In recent years growing attention has been given to the possibility that memory problems of the elderly, both self-reported and observed by spouses or relatives, may be a useful and reliable predictor of the future risk of developing dementia, including AD. The central problem with studies directed at this important question has to do with the definition and diagnosis of MCI. The perception of memory problems differs considerably from individual to individual, and may not always be consistent with that noticed by an observer. In addition, some studies include in the definition of MCI one other aspect of cognitive impairment, so on the one hand there is the so called amnesic MCI, which is just a memory abnormality, and on the other a combination of amnesic MCI and an additional cognitive deficit. An important aspect of all definitions of MCI is the absence of dementia. Sometimes, the assessment is made with a battery of tests, sometimes just with a history and questions. A distinguishing feature of MCI as compared to age-associated memory impairment (normal) is that individuals with the latter do not get worse rapidly—they frequently complain of the same degree of memory problems for a number of years. However, this is not clear cut, and some individuals thought to have MCI actually get better or do not progress to AD.

Evidence from a number of studies does indeed suggest that the presence of MCI significantly increases the probability of developing AD. The increased risk depends on just how MCI is defined, and how accurate the definition matches the patient. It is unclear whether amnesic MCI or MCI with an added cognitive impairment has a greater risk of progressing to AD, although the evidence is in favor of a greater risk for the latter. Recent studies indicate that persons with MCI have as high as a 50% probability of developing AD sometime in the 4 years following the initial diagnosis (26). One study found an annual conversion rate of 8.3%, which is about 38% over four years (28). A study organized by the Mayo Clinic found an annual rate of conversion of 10-12% per year for amnesic MCI patients characterized by a memory complaint abnormal for their age, but with normal activities of daily living, normal general cognitive function, and the absence of dementia (29). In normal subjects one expects less that 2% conversion per year for the group in question. While studies yielding smaller conversion rates than 8-12% per year can be found, it is nevertheless clear that MCI, even when defined to involve just a memory problem, indicates a potential risk that is significant.

Studies have been reported where individuals classified as having MCI but no dementia have for some reason died and their brains have been examined. There are also cases where the brains of individuals free of any signs of MCI have been examined for evidence of AD pathology. What is perhaps surprising is that there were a number of individuals in these two groups where the pathology of AD was clearly and abundantly evident, and yet they showed no signs of dementia (30, 31). In other words, the pathology of AD can presumably develop, in some cases extensively, while the individual remains asymptomatic or develops only MCI. This may be related to the rather short interval between patients presenting with MCI and the development of clear clinical evidence for probable AD, at least for those in which this is indeed the sequence of events (32). In other words, the AD pathology appears to develop over an extended period prior to the MCI diagnosis. Also, in other studies of groups classified as having MCI, a significant percentage have, after several years, reverted to normal, for no apparent reason, even though progression to AD was seen in other members of the cohort (28, 33). Some researchers (32) like to view these early stages as a continuum, where at the beginning there can be AD pathology, or perhaps vascular pathology, or both, and later on MCI can develop, followed by the development of the clinical symptoms of AD. But up to some point the process or processes may either slow, halt, or even reverse without intervention. This broad view is very important because symptoms of MCI, especially amnesic MCI, need not necessarily mean that AD is inevitable.

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