Alzheimer Mythology: A Time to Think Out of the Box

Editorial in JAMDA by John  Morley  and Susan Far

 “If you find yourself caring for a relative with dementia, the chances are you will need help.”

∼Phyllis Logan

The mythology of Alzheimer disease begins with the name. Aloysius Alzheimer described a case of presenile dementia in Auguste Deter in whom he identified plaques and tangles in 1906 at the Tubingen meeting of the Southwest German Psychiatrists and published the paper the next year.1 Madame Deter, besides having presenile dementia and neuropsychiatric symptoms not characteristic of Alzheimer disease as we now know it, had a rare autosomal dominant form due to a presenilin-1 mutation.2 Five months before this, Solomon Carter Fuller, an African American from Liberia, reported a similar case in an older person. He had previously studied with Alzheimer.3 In 1906, Koichi Miyaki published an article in which he studied 25 cerebral cortices from older persons.4Of these, two out of the four with dementia had plaques. In 1907, Oskar Fischer reported on patients with senile dementia who had plaques.5 Kraepelin, when he published his taxonomy of psychiatric disorders, called this form of dementia Alzheimer disease, as Alzheimer worked at his institute in Munich. Not only was this an example of academic one-upmanship, it could also be considered anti-Semitic (Fischer) and racist (Fuller). However, none of these were the first description of the pathology. In 1882, Paul Blocq and George Mannesco, in Paris, reported “round heaps” (plaques) in an aged patient 6and in 1898, Redlich associated the plaques with senile dementia.7 Thus, it could be argued that Alzheimer should not have had this disease named after him, or at least it should have been designated Fischer-Alzheimer disease.

The Cholinergic Hypothesis

In 1976, David Bowen reported cholinergic deficits in patients with Alzheimer disease, and in 1981, Davies and Maloney suggested that the cause of memory deficits in Alzheimer disease was due to degeneration of acetylcholine production in the forebrain group of neurons known as the nucleus basalis of Meynert.8 This gave rise to the cholinergic hypothesis of Alzheimer disease. Unfortunately, it is now recognized that many neurotransmitters act in synergy to enhance cognition.9 Examples of neurotransmitter levels changed in Alzheimer disease are, for example, serotonin, histamine, dopamine, norepinephrine, gamma-amino butyric acid, glutamate, somatostatin, and neuropeptide Y.10 This is clearly part of the explanation for the disappointing results seen with donepezil and other cholinergic esterase inhibitors.11Further, it is recognized that neurotransmitters have a bell-shaped curve of action, so when the dose is increased above the effective dose, they are actually amnestic.12 The original tacrine study recognized this and aimed to find an optimal dose.13 The recent concept of having even higher doses of donepezil to get around patent expiry issues makes very little sense.14 Also, when two neurotransmitter agonists are combined, this needs to be done at lower doses to be effective.9, 15 and 16 The failure of clinicians to take this basic science knowledge into account is mystifying as is the failure to recognize that to treat Alzheimer disease with neurotransmitter agonists or antagonists requires personalized medicine with measurements of the neurotransmitters involved. At this stage, it is safe to say that the cholinergic hypothesis has been woefully inadequate.

Multiple Causes of Dementia

There are numerous causes of dementia.17 Most physicians consider only a few of them. At a minimum, the treatable causes of cognitive impairment need to be considered. These include sleep apnea, hypothyroidism, normal pressure hydrocephalus, depression, polypharmacy, and deficits in vision and hearing.18, 19 and 20

Besides Alzheimer disease, there are four major other causes of dementia:

PART consists of persons with neurofibrillary tangles and no amyloid plaques.21 and 22These patients have more self-reported symptoms and less severe objective dementia. PART is often diagnosed as Alzheimer disease.23 Hippocampal sclerosis causes severe cognitive impairment.24 It is due to cell loss and gliosis in the hippocampus. It is associated with transactive response DNA-binding protein 43 aggregation in the frontotemporal lobe.25 It causes more rapid cognitive decline than Alzheimer disease. It is associated with about 2.5% of dementias in older persons25 and is often misdiagnosed as Alzheimer disease. Four genes have been recognized as being associated with hippocampal sclerosis (GRN, TMEM 106B, ABCC9, and KCNMB2).26 ABCC9 is the sulfonylurea receptor, and as such, may explain the increased cognitive impairment seen in patients with type 2 diabetes receiving sulfonylureas.27

Vascular dementia is characterized by white matter hyperintensities (leukoariosis) on MRI, which are often ignored. Appropriate early treatment of atrial fibrillation with anticoagulation and/or exclusion of the atrial appendage (eg, the WATCHMAN technique) will decrease the rate of cognitive decline. Similarly, treatment of hypertension and cholesterol in middle age will decrease mini-strokes as the person ages.28, 29,30 and 31 Vascular lesions in the brain interfere with brain connections leading to cognitive impairment and cognitive frailty.28, 32, 33 and 34 Vascular lesions also produce oxidative damage leading to increased inflammatory cytokines, which increase amyloid-beta protein leading to cognitive damage, tau phosphorylation, blood–brain barrier damage, and eventually amyloid plaques.35, 36, 37, 38, 39 and 40

Patients with Lewy body dementia have more behavioral symptoms than cognitive decline.41 The symptoms tend to fluctuate through the day, similar to delirium. Patients commonly have sleep disturbances such as sleep apnea and restless legs syndrome. They also have severe autonomic neuropathy. Approximately 20% of persons with dementia have Lewy body dementia.

A recently recognized condition is dementia associated with diabetes. Although epidemiological studies tend to call this Alzheimer disease, pathological studies have failed to confirm this.42 There is a major need to increase studies on this condition and the effect of the new HbA1C levels on dementia.43, 44 and 45 Both elevated and low glucose levels are associated with cognitive impairment.46, 47 and 48

The recognition of so many types of dementia opens the question of whether the failure of drugs to treat Alzheimer disease is due to the fact that most of the people being treated in trials do not have Alzheimer disease (Figure 1).

This is just one of the harms in making everybody believe that most dementia is Alzheimer disease! To be put simply, dementias are the opposite of Occam's razor, that is, they follow Hickam's dictum: Patients can have as many diseases as they please

Does Amyloid-Beta Cause Dementia?

Many years ago, we showed that injecting pharmacological amounts of amyloid-beta into the brain of a mouse causes amnesia.49 and 50 These doses also increase GSK-3β, which phosphorylates tau and damages neuronal connections, damages the blood–brain barrier, produces oxidative damage and, when given over a long time, will produce amyloid plaques.51, 52 and 53

In contrast, physiological doses of amyloid-beta enhance memory.54 and 55 They also increase the release of acetylcholine in the hippocampus. Antibodies and antisenses to amyloid-beta inhibit memory in young mice, while they enhance memory in Alzheimer mouse models.56, 57 and 58 Thus, the physiological role of amyloid-beta is to enhance memory (ie, it is a memory mnemonic).

The question then is how crucial are amyloid plaques to the dementia of Alzheimer disease? It is now clear that a substantial proportion of older persons have amyloid plaques with no evidence of memory disturbance.59 and 60 In addition, the SAMP8 mouse model of Alzheimer disease61 and 62 does not develop plaque until long after it has memory disturbances.63 These findings suggest that amyloid plaque is not essential to the dementing process of Alzheimer disease. We have hypothesized that the amyloid plaque can be compared to a garbage can that removes amyloid-beta as it increases to pathological levels, thus protecting against dementia. Only when there is a large excess of plaque does it cause meaningful brain damage.

Figure 2 provides a schema for the role of amyloid-beta in memory and Alzheimer disease. The amyloid hypothesis is thus alive and well, with the change that pathological overproduction of amyloid-beta causes Alzheimer disease. Lack of amyloid-beta also causes memory problems. This explains why the studies with secretase inhibitors (semagacestat) had negative cognitive effects.64

Infection and Alzheimer Disease

It has long been known that certain chronic infection (eg, tertiary syphilis, AIDS) can cause dementing illnesses.65 and 66 Both Fischer and Alzheimer argued that the senile plaques were due to microorganisms.67Helicobacteria pylori infection has been shown to be associated epidemiologically with dementia. 68 Oral infections have also been associated with Alzheimer disease.69 Lim et al70 provided evidence that life-long exposure to infectious agents predisposes to Alzheimer disease. Recently, a group found that when microorganisms pass through the blood–brain barrier into the brain, they are walled off and eventually become the nucleus for an amyloid plaque.71

As we pointed out in the section on vascular dementia, inflammation leads to release of inflammatory cytokines that cause the increased production of amyloid precursor protein.72 and 73 Cytokines can cross the blood–brain barrier and directly produce cognitive disturbances.38 and 39 Supporting this is the findings that NSAIDs may reduce dementia, but the evidence is weak.74

Traumatic brain injury (TBI) also produces inflammation leading to the production of amyloid plaques and neurofibrillary tangles.75 It is important to recognize that amyloid precursor protein in TBI actually has protective effects on the brain,75 and 76 further supporting a role of amyloid-beta as a physiological memory enhancer.

Figure 2 outlines the neuroinflammatory mechanism for Alzheimer disease. Clearly, modulation of inflammation represents a possible therapeutic approach to preventing Alzheimer disease.

The physical frailty phenotype increases dramatically with aging and is the predictor of disability and death.77, 78, 79, 80, 81, 82 and 83 Not surprisingly, physical frailty is strongly associated with the presence of inflammatory cytokines.84, 85 and 86 Given this, it is not surprising to find a subset of persons who are both frail and have cognitive problems. This has been designated as cognitive frailty. 87, 88 and 89 Persons with cognitive frailty tend to have very poor outcomes.

Motoric cognitive syndrome refers to persons with pre-dementia and slow gait. 90, 91 and 92Gait is strongly related to cognitive function. 93 and 94 In some cases, this is associated with a dual tasking deficit—the inability to walk and talk at the same time. 95 and 96

Lifestyle Modifications Are an Important Component of the Management of Cognitive Dysfunction

The data supporting a Mediterranean diet to slow the onset of dementia appear to be relatively strong.97, 98, 99 and 100 Both in animals and humans, interventional studies suggest a positive effect of extra-virgin olive oil.101 and 102 This is due to phenyls and, in other studies, fruits with polyphenyls (eg, blueberries) also appear to be protective.103 and 104 Epidemiologic studies support the increased intake of fish consumption as decreasing the incidence of Alzheimer disease.105, 106 and 107 Similarly, consumption of n-3 polyunsaturated fatty acids seems to have a minor effect on reducing dementia, and this is supported by animal studies.108 The MAPT study shows support for the use of omega-3 fatty acids and exercise for preventing Alzheimer disease.109

The data to support exercise as protective of cognitive function is more variable, but as exercise is overall positive, it would seem to be reasonable to recommend exercise as well.110, 111, 112, 113 and 114 This is supported by the FINGER study, which used a set of interventions such as Mediterranean diet, exercise, socialization, computer games, and treatment of vascular disease.115

Cognitive stimulation therapy has been shown to work at least as well as donepezil for the treatment of moderate dementia.116, 117, 118, 119 and 120 It is also considered to be cost effective.121 A slightly different approach in Japan has also worked.122 Similarly, reminiscence therapy appears to have a positive effect on quality of life.123, 124, 125 and 126

Overall, there is strong evidence for institutionalizing lifestyle modifications for persons with mild cognitive impairment and early dementia.

Screening and/or Case Finding for Dementia

When physicians are treating patients, they need to recognize whether they have cognitive impairment. It is well recognized that physicians are not good at recognizing dementia.127 For this reason, all older patients seeing a physician need to have their cognitive status checked at least once a year. This can be done as part of their annual wellness visit.128 Both the MOCA and the SLUMS are excellent screening tools but take between 7 to 12 minutes to administer.129, 130, 131, 132 and 133 For this reason, we developed the Rapid Cognitive Screen, which is excellent at detecting dementia, acceptable for recognizing mild cognitive impairment, and takes 2 ½ minutes to administer.134

In our experience in St. Louis, about one-third of older persons do not have a primary care physician, and over half of patients with dementia have not had it recognized by their physician. Importantly, persons with early-stage dementia are still capable of completing their advanced directives.135 These individuals need to receive lifestyle advice, treatment for reversible causes of dementia, and in some cases, oversight to prevent poor outcomes (eg, driving accidents, shooting another, getting lost, starting fires). For this reason, we strongly support community screening as is supported by the Alzheimer Association.136 As pointed out in the Brain Health article, screening needs to be done in an appropriate manner. 137 We recognize that many physicians dealing with Alzheimer disease disagree with this, but we struggle to understand their reasons. 138, 139, 140, 141,142, 143, 144, 145 and 146

In this editorial, we have delved into some controversial areas regarding Alzheimer disease. In many cases, leaders in the field get hung up on a single theory and fail to recognize the broadness of the causes of dementia and even the causes of Alzheimer disease. Many people in trials for Alzheimer disease do not have it. Tau scanning should improve diagnosis, but distinguishing between PART and Alzheimer disease will not be possible.147 This editorial is asking for a better diagnosis of the multiple dementias, a recognition that there are many causes of Alzheimer disease and plaques may be an epiphenomenon, and increased case finding for cognitively impaired persons in the community who are carefully studied for reversible causes and receive advice on lifestyle modification. The editorial is deliberately provocative hoping to develop a dialog in the field. Finally, what we now call Alzheimer disease should be called “hyper-beta-amyloidosis” and divided into type I (young onset, multiple genetic types) and type II (older onset) (Fig. 1 and Fig. 2). This would make much more sense than continuing to give credit erroneously to one person for the discovery of the disease.