It, preventing the development of Alzheimers disease and dementia (Figure 18-9A).

in the case
of bad Apo-E, a genetic abnormality in the formation of Apo-E causes it to be ineffective in
how it binds to beta amyloid. This causes beta amyloid to be deposited in neurons, which then
goes on to demage the neurons and cause Alzheimers disease.

Genes coding for Apo-E are associated with different risks for Alzheimers disease.
There are three allel (or copies) of this gene coding for this apolipoprotein called E2,E3, and E4.
For example, a gene on cromosom 19 that codes Apo-E is linked to many case of late-onset
Alzheimers disease. Apo-E 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 Alzheimers disease,
and Alzheimer patients with E4 have more amyloid deposits.

Are the predementia states?

Amnestic mild cognitive impairment (MCI)

MCI is concept difined memory impairment compared to age-matched peers, with normal
cognitive function in other domains (no aphasia, apraxia, agnosia, or executive dysfuntions) and
no functional evidence of actual dementia. Is this a precursor to Alzheimers disease, part of
normal aging, or a mild and very slowly progressive form of alzheirmers disease (Alzheimwr
light)? These questions are now being vigorously debated by experts.

What is normal aging? Over half of elderly resident living in the community complain
of memory impairment. They have four common complaints: compared to their functioning of 5
or 10 year ago, they experience diminished ability (1) to remember names, (2) to find the correct
word, (3) to remember where objects are located, (4) to concentrate. When such complains occur
in the absence of overt dementia, depression, anxiety disorder, sleep/wake disorder, pain
disorder, or AHDH (attention deficit hyperactivity disorder), the condition is sometimes called
MCI, age-asssociated memory impairment, or cognitive impairment no dementia (CIND). It this
likely MCI is not a benign condition, as studies show that between 6 and 15 percent of these
patients convert to a diagnosis of dementia every year; after 5 yaers, about half meet the criteria
for dementia; after 10 years or autopsy, up to 80 percent will prove to have or have had
Alzheimers disease.

Given the possibility of disease-modifying treatments on the horizon for Alzheimers

disease, there is intense interest in finding a way to recognize this illness early, at the stage of
MCI or even earlier, so that treatmets can begin early rather than after significant irreversible
brain demage has already occurred. If such a state of pre-Alzeheimers disease or early
Alzheimers disease could be recognized, it would allow disease-modifying treatments to be
administered at the stage of presymtomatic/prodromal disease (Figure 18-10). This notion is also
discussed for schizophrenia in Chapters 9 and 10 and illustrated in Figure 9-44 and 10-120. The
idea is not to remove curren symptoms but no prevent future symptoms and deterioration.
 There are many methodological and logistical problems with conducting such studies in
both schizophrenia and Alzheimers disease: deciding what subjects to enter into that study; the
expense (because these studies need huge numbers of patients and take a very long time to
conduct); the problems in defining satisfactory endpoints (when do you have early schizophrenia
or Alzheimers disease, etc.); and the risk potentially exposing these not destined to develop the
disease to drugs with side effects.

A number of psychopharmacological agents have been tested for their potential as

disease-modifying agents in Alzheimers disease, but none has yet proven effective. This
includes various antioxidants, anti-inflammatory agents, statints, the cholinesterase inhibitors
used to treat the symptoms of patients who already have Alzheimers disease, vitamin E,
estrogen, the MAO inhibitors selegiline, and others. Currently there are a number of novel
psychopharmacological agents based upon the amyloid cascade hypothesis in early testing as
disease-modifying agents for Alzheimers disease.

It is interesting to note that so far, the only intervention that has been consistently
replicated as a disease-modifying treatment to diminish the risk for MCI or Alzheimers disease
and that can slow the progressionof the conditions is cognitive activity. Thus, exercising the
brain in a use it or lose it paradigm appears effective when leisure activities include reading,
writing, crossword puzzles, board or card games, group discussions, and playing music. Even
physical exercise may be effective, including tennis, golf, swimming, bicycling, dancing, group
exercises, team games, walking, climbing more than two flights of stairs, and babysitting. It is
now known that the brain makes new neurons throughout life, as discussed in Chapter 2 and
illustrated in Figures 2-3 and 2-4. Howefer, it appears that only if you actively engage in learning
will these cells survive, whereas the mentally lazy may lose these new neurons.

In order to help identify patients with presymptomatic or prodromal/early symptomatic

Alzheimers disease, several diagnostic test are being evaluated, from novel neuroimaging
techniques capable of measuring amyliod, to PET scans of neuronal activity in fontal versus
temporal cortical area, to sophisticated neuropsychological evaluations, to the measurement of
genetic risk factors, including Apo-E (Figure 18-10).

Depression: harbinger of dementia?

Depression can not only be mistaken for dementia but can also precede the onset of dementia
(Figure 18-11). One of the difficult diagnostic and therapeutic management areas of modern
psychopharmacology is depression in the elderly. In such patients, dementia and depression can
be interrelated in many complex ways. When depression occurs in late life, whether it is a
recurrent episode in a patient with a lifetime of episodes or a firs episode with onset in late life, a
major depressive episode can actually present with prominent cognitive symptoms, especially
apathy, lack of interest, and slowing of information processing rather than depressed mood and
sadness. Depression with lack of interest or sadness can also occur in patients with established
dementia, in patients whose depression represents a prodrome to dementia (Figure 18-11), and in
those who ultimately prove to have reversible cognitive impairments from pseudodementia or
the dementia of depression.

Late-onset depression may be a dysfunction of prefrontal circuits, including the pre-

frontal CSTC circuits discussed extensively in relation to executive dysfunction in Chapter 17
and illustrated in Figures 17-3 and 17-4. Some experts call the clinical syndrome associated with
hypothetical prefrontal striatal dysfunction in the elderly the DED (depression executive
dysfunction) syndrome. This syndrome is characterized by psychomotor retardation, reduced
interest in activities, impaired insight, and pronounced behavioral disability.

The DED syndrome may progress to a diagnosable dementia and may have a poor response to
traditional antidepressants, but it may respond to dopaminergic agents (such as dopamine
agonists, amantadine, modafinil, or even stimulants in selected cases) or to cholinergic agents
(such as cholinesterase inhibitors).

Effective treatment of depression in the elderly can improve cognitive function, but
unlike younger patients, many depressed elderly will not return to their premorbid level of
cognitive performance, especially their memory and executive functioning. In such cases, the
depression may be heralding the onset of Alzheimers disease (Figure 18-11). Up to half of
elderly patients who present with depression and cognitive impairment will prove within 5 years
to have cognitive impairment that is irreversible. Cognitive impairment in depression of the
elderly may be associated with poor or very slow antidepressant response (12 weeks or longer);
however, recent findings with SNRIs are somewhat more encouraging, in that both mood and
cognitive symptoms can improve notably. Patients with vascular depression may benefit bay
prevention of further ischemic events from treatments with antithrombotic agents such as aspirin
and clopidogrel. Patients whose depression may represent a prodrome to Alzheimers disease
(Figure 18-11) may experience symptomatic benefit, such as improvement of apathy and
memory as well as mood, from treatment with cholinesterase inhibitors, although these agents
are not approved for this use.

Symptomatic treatments for dementia

Acetylcholine and the pharmacological basis of cholinesterase treatments for dementia

Many of the current treatments for symptoms of dementia are based upon boosting the
availability of the neurotransmitter acetylcholine. Prior to discussing these treatments, we will
review the pharmacology of acetylcholine. The principal cholinergic pathways are introduced in
Chapter 7 and illustrated in Figure 7-11 and 7-12.

Acetylcholine is formed in cholinergic neurons from two precursors: choline and acetyl
coenzyme A (AcCoA) (Figure 18-12). Choline is derived from dietary and intraneuronal sources,
and AcCoA is made from glucose in the mitochondria of the neuron. These two subtrates interact
with the synthetic enzyme choline acetyl transferase (CAT) to produce the neurotransmitter
asetylcholine (Ach).

Achs actions are terminated by one of two enzymes, either acetylcholinesterase (AChE)
or butyrylcholinesterase (BuChE), sometimes also called pseudocholinesterase or nonspecific
cholinesterase (Figure 18-13). Both enzymes convert ACh into choline, which is then
transported back into the presynaptic cholinergic neuron for resynthesis into ACh (Figure 18-13).
Although both AChE and BuChE can metabolize ACh, they are quite different in that they are
encoded by separate genes and have different tissue distributions and substrate patterns. There
may be different clinical effects of inhibiting these two enzymes as well. High levels of AChE
are present in brain, especially inn neurons that receive ACh input (Figure 18-13). BuChE is
also present in brain, especially in glial cells (Figure 18-13). As discussed below, some
cholinesterase inhibitors specifically inhibit AChE, whereas others inhibit both enzymes. It is
AChE that is thought to be the key enzyme for inactivating ACh at cholinergic synapses (Figure
18-13), although BuChE can take on this