Future Treatments of Memory Loss, Alzheimer’s Disease, and Dementia

Because of the rapid aging of the population and the accompanying increase in the prevalence of Alzheimer’s disease, there is enormous interest from both the federal government and private industry in developing new and better treatments. In general, these treatments are aimed at two targets: treating the symptoms of Alzheimer’s disease and attempting to slow the progression of the disease.

Quick Start

Symptomatic and disease-modifying treatment	• Alzheimer’s disease can be treated either to improve symptoms and function or to slow disease progression. • Symptomatic treatments work by altering neurotransmitter function. • Most disease-modifying treatments are aimed at decreasing β-amyloid protein in the brain. • Some disease-modifying treatments in development are directed against neurofibrillary tangle formation.
Disease-modifying treatments: amyloid plaques	• The amyloid cascade hypothesis describes how a buildup of β-amyloid can lead directly to amyloid plaques, neurofibrillary tangles, neurotransmitter disruption, and dementia. • Approaches to decrease β-amyloid have included active immunotherapy, passive immunotherapy, reducing the formation, accumulation, or oligomerization of β-amyloid, and blocking the enzymes that cleave β-amyloid from amyloid precursor protein. • No disease-modifying treatments have yet proven efficacious. • Many disease-modifying treatments are currently in clinical trials. • Disease-modifying treatments may need to be started at the earliest signs of β-amyloid in the brain—perhaps years or decades prior to the onset of symptoms.
Disease-modifying treatments: neurofibrillary tangles	• As tangles are further downstream in the cascade that leads to clinical symptoms, treatments directed against tangles may be more efficacious in patients who have already developed clinical Alzheimer’s disease than treatments directed against β-amyloid. • Tangle formation may be the final common pathway in many degenerative diseases and thus treatments directed against tangles may also be efficacious against other dementias such as frontotemporal dementia and chronic traumatic encephalopathy.

Strategies to Treat the Symptoms of Alzheimer’s Disease

As discussed in Chapter 15 , patients for whom we prescribe a cholinesterase inhibitor, memantine, or a combination of the two often ask how these medications work and what else can be done. After explaining the mechanism of these standard, FDA-approved medications, we often have a brief discussion of some of the types of treatment that are currently being developed. There are two basic reasons why we discuss future treatments. One is to give patients (and their children who are often worried about developing Alzheimer’s disease when they are older) hope for the future. The second is that some patients may be interested in participating in one of the numerous clinical trials of novel medications that are being developed for Alzheimer’s disease, available in many large medical centers and Alzheimer’s disease specialty clinics/clinical research centers.

Additional Symptomatic Treatments

One strategy to further help patients with Alzheimer’s disease is to facilitate neuronal transmission, that is, communication between brain cells. The cholinesterase inhibitors and memantine (Namenda) improve the function of neurons that use acetylcholine, glutamate, and dopamine as their neurotransmitters. There are, however, other neurotransmitter systems in addition to these that can be augmented. It is now well documented that Alzheimer’s disease affects many neurotransmitter systems. Table 19-1 summarizes these transmitter systems. At some point we might envision a drug cocktail that will boost the level of multiple neurotransmitter systems, thereby facilitating cognition. We are now at the beginning of this type of strategy when we combine memantine with a cholinesterase inhibitor. We may become sufficiently sophisticated to tailor the cocktail based on the specific symptoms that the patient is experiencing or even the patient’s genotype.

TABLE 19-1

Neurotransmitters Depleted in Alzheimer’s Disease

Transmitter System	Degree of Involvement in Alzheimer’s Disease	Approved Medications	Clinical Trials Ongoing?
Acetylcholine	✓✓✓	donepezil (Aricept), rivastigmine (Exelon), galantamine (Razadyne)	✓✓✓
Glutamate	✓✓✓	memantine (Namenda)	✓
Serotonin	✓✓	—	✓✓✓
Norepinephrine	✓✓	—	✓
Dopamine	✓	memantine (Namenda)	✓
GABA	✓	—	✓
Peptides	✓	—	✓

There is currently considerable research ongoing aimed at developing additional symptomatic treatments. Over the past few years, clinical trials have been undertaken to determine the effects of drugs that affect transmitter systems including serotonin, norepinephrine, dopamine, somatostatin, histamine, GABA, and others, in addition to acetylcholine and glutamate.

Disease-Modifying Treatments

Development of symptomatic treatments notwithstanding, the major focus of new drug development for Alzheimer’s disease is on disease-modifying drugs (sometimes called mechanism-based treatments). That is, drugs that address the underlying cause of the disease and in doing so prevent cell death. If this strategy is successful, then the progression of the disease could theoretically be halted. If this strategy could be combined with both early diagnosis and the use of symptomatic drugs, we could be on the horizon of successfully managing this disease.

Although the cause of Alzheimer’s disease is unknown, there are a number of promising hypotheses regarding the pathogenesis of the disease, and these hypotheses have led to the development of potential disease-modifying drugs. The leading view of the initial cause of cell death in Alzheimer’s disease is the amyloid cascade hypothesis.

Alzheimer’s Initial Observations

When Alois Alzheimer had the opportunity to examine the brain of his first patient, Anna O, in 1906, he characterized the two forms of pathology that are the neuropathological hallmarks of the disease that now bears his name: senile plaques and neurofibrillary tangles.

Senile plaques appear to have a fluffy central core surrounded by thick irregular processes ( Fig. 19-1 ). The central core is made up of a sticky protein called amyloid, and the surrounding material is a combination of dystrophic processes (axons and dendrites) and astrocytes. These plaques are primarily found in the association areas of the frontal, parietal, and temporal cortices and the piriform cortex, hippocampus, and amygdala ( Fig. 2-1 ). Neurofibrillary tangles are intraneuronal cytoplasmic structures that are composed of paired filaments. Under the microscope they look like skeins of yarn ( Fig. 19-1 ). These tangles appear to consist primarily of a hyperphosphorylated form of the microtubule-associated protein tau. Microtubules are one of three major constituents of the neuronal cytoskeleton; neurofilaments and microfilaments are the other two. All of these can be thought of as infrastructural elements of neurons that participate in functions such as axonal transport and maintenance of the structural integrity of the cell. In Alzheimer’s disease, neurofibrillary tangles are present in the cortex, hippocampus, amygdala, nucleus basalis of Meynert, dorsal raphe, other brainstem nuclei, and ultimately in many other brain regions.

(See Chapter 4 for additional information on senile plaques and neurofibrillary tangles.)

Baptists vs. Tauists

There has been ongoing debate regarding which form of pathology, senile plaques or neurofibrillary tangles, is the primary culprit in Alzheimer’s disease. The debate has become known as the “baptists” versus the “tauists.” The baptists favor the view that β-amyloid protein and β-amyloid plaques are the culprits that start an inexorable cascade that ultimately destroys neurons. They are referred to as baptists because β-amyloid protein (or plaque) can be shortened to βAP, but is now more commonly known as β-amyloid or Aβ. The tauists put forth the view that neurofibrillary tangles are the primary cause of cell death. They are called tauists because of the role of tau in forming the tangles.

As with many scientific debates, there is often a synthesis of the two competing views and this now appears to be the case in the baptist vs. the tauist debate. The emerging view is that the earliest pathological event is the formation of amyloid. There is now evidence that the accumulation of brain amyloid precedes the emergence of cognitive symptoms by 15 and perhaps 20 years ( ). There is also evidence that β-amyloid is toxic to neurons, but the primary culprit in cell death is now believed to hyperphosphorylated tau. Hyperphosphorylated tau breaks down the infrastructure of the neuron and in doing so leads to neuronal death. The current view further hypothesizes that through mechanisms that are not fully understood, β-amyloid promotes the emergence of hyperphosphorylated tau and that once tau invades a neuron it can spread throughout the brain from neuron to neuron ( ).

This hypothesis has focused the search for disease-modifying treatments. Currently most of this effort is focused on β-amyloid, but there is also now increasing efforts to address the role of tau in the progression of Alzheimer’s disease.

The Amyloid Cascade Hypothesis

The amyloid cascade hypothesis starts with the premise that the earliest sign of the pathogenesis of Alzheimer’s disease is the accumulation of toxic forms of amyloid. It then follows that the focus of treatment of disease-modifying drugs is to slow and eventually stop the accumulation of amyloid.

Figure 4-9 summarizes the amyloid cascade hypothesis ( ; ; ). As Figure 4-9 shows, the initial assumption is that different gene defects can lead, either directly or indirectly, to an increase in toxic forms of β-amyloid. This increase may be due to either overproduction of or failure to clear these toxic forms of amyloid. Gradual accumulation of aggregated β-amyloid protein leads to a multistep cascade that includes inflammation, neuritic and synaptic changes, neurofibrillary tangles, neurotransmitter loss, and gliosis, and ultimately results in cell death and dementia.

β-amyloid is a small piece of a much larger protein called the amyloid precursor protein (APP). The APP is a transmembrane protein that, when activated, is cut into smaller segments which operate either inside or outside the neuron. There are several ways that the APP can be cut, one of which leads to the production of β-amyloid ( Figs. 19-2 and 4-11 ).

There is considerable evidence to support the amyloid cascade hypothesis, for example:

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In a few hundred extended families worldwide, researchers have discovered mutations in genes that virtually guarantee an individual will develop Alzheimer’s disease at a young age. Each of these abnormal genes increases β-amyloid production (those in the APP, presenilin 1, or presenilin 2).
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All Alzheimer’s disease patients have amyloid plaque counts that far exceed those found in normal aging.
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Down’s syndrome patients, who invariably develop Alzheimer’s disease pathology by age 50, produce too much β-amyloid protein from birth (presumably because they have a third copy of the gene coding for the APP, found on chromosome 21).
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β-amyloid fibrils damage neurons in culture and activate brain inflammatory cells (microglia).
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It is hypothesized that β-amyloid can also induce hyperphosphorylated tau which leads to the formation of neurofibrillary tangles and that these tangles can spread from neuron to neuron throughout the brain.

Despite this evidence, the amyloid cascade hypothesis is still only a hypothesis, and as with all hypotheses there are unanswered questions. Nevertheless, the amyloid cascade hypothesis continues to be the most widely accepted view of the pathogenesis of Alzheimer’s disease and as such amyloid continues to be a major therapeutic target. Considerable research is now ongoing in an attempt to develop drugs that will intervene in this cascade and in doing so slow (or even stop) the progression of the disease. Some of these drugs act to directly modulate β-amyloid while others are aimed at the downstream effects of β-amyloid plaque such as inflammation. As discussed in the following sections, with the recognition that amyloid may be present in the brain 15–20 years prior to the onset of symptoms, the strong trend in anti-amyloid, disease-modifying clinical trials is to push these therapies earlier and earlier in the disease from early Alzheimer’s disease, to mild cognitive impairment, to treating people who do not exhibit any symptoms but have amyloid in the brain as evidenced by amyloid PET scans ( Fig. 2-6 ).

Amyloid-Directed Treatments

There are three major ongoing approaches to intervening in the amyloid cascade ( Figs. 4-9 , 4-11 , 19-2 , 19-3 ). The first, secretase inhibitors, involves blocking the formation of β-amyloid by interfering with the enzymes that cleave the amyloid precursor protein in a manner that yields the toxic form of β-amyloid. The second approach, anti-aggregants, is aimed at preventing the aggregation of single strands of β-amyloid (monomers) into units containing multiple strands (oligomers) of the β-amyloid. There is some evidence that, although monomers are not neurotoxic, as few as two aggregated strands (dimers) may be ( ). The third strategy, vaccines, involves removing the neuronal plaques, which consist of an aggregated β-amyloid core surrounded by parts of dying neurons.