Dementia and its treatment
This chapter will provide a brief overview of the various causes of dementias and
their pathologies, including the most recent diagnostic criteria and the emerging
integration of biomarkers into clinical practice for Alzheimer’s disease. Full clinical
descriptions and formal criteria for how to diagnose the numerous known dementias
should be obtained by consulting standard reference sources. The discussion here will
emphasize the links between various pathological mechanisms, brain circuits, and neurotransmitters
and the various symptoms of dementia, with an emphasis on Alzheimer’s disease. The
goal of this chapter is to acquaint the reader with ideas about the clinical and biological
aspects of dementia and its currently approved treatments as well as new treatments
that are on the horizon. The emphasis here is on the biological basis of symptoms
of dementia and of their relief by psychopharmacologic agents, as well as on the mechanism
of action of drugs that treat these symptoms. For details of doses, side effects,
drug interactions, and other issues relevant to the prescribing of these drugs in
clinical practice, the reader should consult standard drug handbooks (such as Stahl’s Essential Psychopharmacology: the Prescriber’s Guide).
Causes, pathology, and clinical features of dementia
Dementia consists of memory impairment (amnesia) plus deficits in either language
(aphasia), motor function (apraxia), recognition (agnosia), or executive function
such as working memory and problem solving. Personality changes can also be present,
Table 13-1 Pathological features of selected degenerative dementias

Table 13-2 Not all memory disturbance is Alzheimer’s disease: clinical features of selected degenerative
dementias

sometimes even before memory impairment begins. There are many causes of dementia
(
Tables 13-1 through
13-3), and the unique pathologies associated with some of the major dementias are listed
in
Table 13-1. Knowing the pathology does not mean that a treatment is available, as it is often
not evident how to translate information about brain pathology into pharmacological
treatments. The best hope currently is in the area of amyloid pathology, where new
treatments under investigation are attempting to interfere with amyloid processing
in Alzheimer’s disease, as will be discussed later in this chapter.
Just because a patient develops memory disturbance does not mean it is Alzheimer’s
disease (Table 13-2). Alzheimer’s dementia is perhaps the best-known and commonest dementia, but it is often the other symptoms
associated with memory loss that help make the diagnosis clinically (Table 13-2). Just to complicate things, many patients have mixed types of dementia, particularly
Alzheimer’s dementia plus dementia with Lewy bodies, or Alzheimer’s dementia plus vascular dementia (Figure 13-1). Such cases
are complicated to diagnose clinically, and definitive diagnosis sometimes must await
autopsy. Most dementias are really pathological diagnoses, not clinical diagnoses.
Table 13-3 Nondegenerative dementias

A wide variety of dementias are considered nondegenerative, and these are listed in
Table 13-3. Many of these are treatable upon discovering the underlying cause, but others are
not. Extensive clinical evaluation and laboratory testing must rule out these causes
prior to concluding that a case of dementia is due to Alzheimer’s disease.
Alzheimer’s disease: β-amyloid plaques and neurofibrillary tangles
Without the introduction of disease-modifying treatments, Alzheimer’s disease is poised
for an exponential increase throughout the world, with projections that it will quadruple
over the next 40 years to affect 1 in every 85 people on earth: over 100 million people
by 2050. Fortunately, new treatments are being designed to interfere with various
known pathological processes, particularly the formation of amyloid plaques, in an
attempt to halt or slow disease progression in Alzheimer’s disease before neurons
are irretrievably lost. To understand the current diagnostic criteria for Alzheimer’s
disease, how and why biomarkers are being integrated into the diagnosis of this disorder,
and the rationale behind the hot pursuit of new therapeutics, it is necessary to understand
how the two hallmarks of this disorder, amyloid plaques and neurofibrillary tangles,
are thought to be formed in the brain in Alzheimer’s disease.
The amyloid cascade hypothesis
The leading contemporary theory for the biological basis of Alzheimer’s disease centers
around the formation of toxic amyloid plaques from peptides due to the abnormal processing
of amyloid precursor protein (APP) into toxic forms of Abeta (Aβ) peptides (Figures 13-2 through 13-9). Why do we make Aβ in the first place? Although this is not fully understood, nontoxic
Aβ peptides have antioxidant properties, can chelate metal ions, regulate cholesterol
transport, and may be involved in blood vessel repair, as a sealant at sites of injury
or leakage, possibly protecting from acute brain injury. Hypothetically, Alzheimer’s
disease is a disorder in which toxic Aβ peptides are formed, leading to deposition
of amyloid plaque in the brain, with the ultimate destruction of neurons diffusely
throughout the brain, somewhat analogous to how the abnormal deposition of cholesterol
in blood vessels causes atherosclerosis.
Thus, Alzheimer’s disease may be essentially a problem of too much formation of Aβ
amyloid-forming peptides, or too little removal of them. One idea is that neurons in some patients destined to have Alzheimer’s disease have
abnormalities either in genes that code for a protein called amyloid precursor protein
(APP), or in the enzymes that cut this precursor into smaller peptides, or in the
mechanisms of removal of these peptides from the brain and from the body. APP is a
transmembrane protein with the C-terminal inside the neuron and the N-terminal outside
the neuron. One pathway for APP processing does not produce toxic peptides and involves
the enzyme α-secretase (
Figure 13-2). Alpha-secretase cuts APP close to the area where the protein comes out of the membrane,
forming two peptides: a soluble fragment known as α-APP and a smaller 83-amino-acid
peptide that remains embedded in the membrane until it is further cleaved by a second
enzyme acting within the neuronal membrane, called γ-secretase (
Figure 13-2). That enzyme produces two smaller peptides, p7 and p3, which are apparently not
“amyloidogenic” and therefore not toxic (
Figure 13-2).
Another pathway for APP processing can produce toxic peptides that form amyloid plaques
(i.e., “amyloidogenic” peptides). In this case a different enzyme, β-secretase, cuts
APP a little bit further away from the area where APP comes out of the membrane, forming
two peptides: a soluble fragment known as β-APP and a smaller 91-amino-acid peptide
that remains embedded in the membrane until it is further cleaved by γ-secretase within
the membrane (Figure 13-3). This releases Aβ peptides of 40, 42 or 43 amino acids that are “amyloidogenic,”
especially Aβ42 (Figure 13-3).
In Alzheimer’s disease, genetic abnormalities may produce an altered APP that, when
processed by this second pathway involving β-secretase, produces smaller peptides
that are especially toxic. Individuals who do not get Alzheimer’s disease may produce
peptides that are not very toxic, or may have highly efficient removal mechanisms
that prevent neuronal toxicity from developing. The amyloid cascade hypothesis of
Alzheimer’s disease therefore begins with an APP that is hypothetically genetically
abnormal, or genetically or environmentally abnormal in the way it is processed, so
that when it is cut into smaller peptide fragments too many toxic peptides are made,
accumulate, and form neuron-destroying amyloid plaques, i.e., amyloidosis, and neurofibrillary
tangles. Hypothetically, this process triggers a lethal chemical cascade that ultimately
results in Alzheimer’s disease (Figures 13-3 through 13-8).
Specifically, abnormal genes or other influences cause the formation of an altered
APP, or altered processing into too many toxic Aβ42 peptides (Figure 13-4). Next, the Aβ42 peptides form oligomers (a collection of a few copies of Aβ42 assembled
together: Figure 13-5). These oligomers can interfere with synaptic functioning and neurotransmitter actions
such as those of acetylcholine, but they are not necessarily lethal to the neurons
at first. Eventually, Aβ42 oligomers form amyloid plaques, which are even larger clumps
of Aβ42 peptides stuck together with a number of other molecules (Figure 13-6). A number of nasty biochemical events then occur, including inflammatory responses,
activation of microglia and astrocytes, and release of toxic chemicals including cytokines
and free radicals (Figure 13-6). These chemical events then hypothetically trigger the formation of neurofibrillary
tangles within neurons by altering the activities of various kinases and phosphatases,
causing hyperphosphorylation of tau proteins, and converting neuronal
microtubules into tangles (
Figure 13-7). Finally, widespread synaptic dysfunction from Aβ42 oligomers, neuronal dysfunction
and death from formation of amyloid plaques outside of neurons and neurofibrillary
tangles within neurons leads to diffuse neuronal death (
Figure 13-8) and regional expansion of neuronal destruction in the cortex, causing the relentless
progression of Alzheimer’s symptoms of amnesia, aphasia, agnosia, apraxia, and executive
dysfunction. Some investigators believe that Alzheimer’s disease may spread from neuron
to neuron, with pathological phosphorylated tau transported down axons, released at
synapses and then taken up by neighboring cells. Pathological tau possibly then latches
onto normal tau in the connected neurons, triggering the formation of new pathological
mis-folded tau, from one affected neuron to the next
.
Support for the amyloid cascade hypothesis comes from genetic studies of those relatively
rare inherited autosomal dominant forms of Alzheimer’s disease. Sporadic (i.e., noninherited)
cases account for the vast majority of Alzheimer’s disease cases, but inherited cases
can provide clues for what is wrong in the usual sporadic cases of Alzheimer’s disease.
Rare familial cases of Alzheimer’s disease have an early onset (i.e., before age 65)
and have been linked to mutations in at least three different chromosomes: 21, 14,
and 1. The mutation on chromosome 21 codes for a defect in APP, leading to increased
deposition of β-amyloid. Recall that Down’s syndrome is also a disorder of this same
chromosome (i.e., trisomy 21), and virtually all such persons develop Alzheimer’s
disease if they live past age 50. A different mutation on chromosome 14 codes for
an altered form of a protein called presenilin 1, a component of the γ-secretase enzyme
complex. A third mutation, on chromosome 1, codes for an altered form of presenilin
2, a component of a different form of γ-secretase. It is not yet clear what if anything
these three mutations in the rare familial cases tell us about the pathophysiology
of the usual sporadic, nonfamilial, and late-onset cases of Alzheimer’s disease. However, they all point to abnormal processing of APP into amyloidogenic β-amyloid
peptides as a cause for the dementia, consistent with the amyloid cascade hypothesis.
Theoretically, different abnormalities in amyloid processing may occur in sporadic
Alzheimer’s disease from those identified in inherited cases, and there may even be
multiple abnormalities that could be responsible for sporadic Alzheimer’s disease
as a final common pathway, but the evidence nevertheless implicates something in the
amyloid cascade that goes wrong in Alzheimer’s disease. If so, this implies that preventing
the formation of amyloidogenic peptides could prevent Alzheimer’s disease.
ApoE and risk of Alzheimer’s disease
A corollary to the amyloid cascade hypothesis is the possibility that something may
be wrong with a protein that binds to amyloid peptides in order to remove them (Figure 13-9). This protein is called apolipoprotein E (ApoE). In the case of “good” ApoE, it
binds to β-amyloid peptides and removes them, hypothetically preventing the formation
of Alzheimer’s disease and dementia (Figure 13-9A). In the case of “bad” ApoE, a genetic abnormality in the formation of ApoE causes
it to be ineffective in how it binds to β-amyloid peptides. This causes amyloid plaques
to be formed and deposited around neurons, which goes on to damage neurons and cause
Alzheimer’s disease (Figure 13-9B).
Genes coding for ApoE are associated with different risks for Alzheimer’s disease.
There are three alleles (or variants) of this gene coding for this apolipoprotein
called E2, E3, and E4, and everyone has two alleles. The E4 variant on chromosome
19 (“bad” ApoE) is linked to many cases of late-onset Alzheimer’s disease, the usual
form of this
illness. ApoE is associated with cholesterol transport and involved with other neuronal
functions including repair, growth, and maintenance of myelin sheaths and cell membranes.
Having one or two copies of E4 increases the risk of getting Alzheimer’s disease.
In fact, some studies show that you have a 50–90% chance of developing Alzheimer’s
disease by age 85 if you are an E4 homozygote (i.e., you have two copies of E4); a
45% chance if you are a heterozygote for E4, versus the risk in the general population
at 20%. Alzheimer’s patients with the E4 gene also have more amyloid deposits and
progress more rapidly to dementia than those without the E4 gene. The E2 variant may
actually be somewhat protective.