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There is evidence for alterations in monoaminergic neurotransmitter functioning and brain metabolism underlying depression in AD. For example, there is evidence for selective loss of 5HT1A receptors in the hippocampus  as well as loss of noradrenergic neurons in locus coeruleus and serotoninergic neurons in the raphe nucleus.

These findings represent additional functional loss of serotonergic neurotransmission over and above the substantial losses observed in AD in general  which selectively affect 5HT2A receptors in early AD . However, basal forebrain cholinergic neurons are relatively spared in depressed patients with AD .

Additionally, there is evidence for decreased gamma amino butyric acid (GABA) levels and greater number of GABA (A) receptors in depressed patients with AD .

Studies of genetic polymorphisms in serotonin and dopaminergic transporters and receptors have not distinguished depressed versus non-depressed patients with AD. Zahodne and colleagues reported that depression in mild cognitive impairment (MCI) was associated with reduced cortical thickness in the entorhinal cortex at baseline and accelerated atrophy in the anterior cingulate cortex.

They interpreted this to mean that depression was associated with the overall rate of neurodegeneration in AD or with reduced cognitive reserve. Several studies have demonstrated lower cerebral glucose metabolism in depressed versus non-depressed patients with AD in the frontal (dorsolateral prefrontal cortex, superior frontal gyrus, and anterior cingulate gyrus) or parietal cortex (post-central gyrus and superior and inferior lobule) .

One study observed that lower 5-HTT transporter density was correlated with greater depression symptom severity . These findings are in contrast to late-life major depression, including the observations of greater white matter hyperintensities, increased cortical glucose metabolism, and 5-HTT and 5-HT1A receptor loss, reviewed in Khandai and Aizenstein  (2013) and Hirao and Smith (2014).

Thus, the evidence indicates that decreased monoaminergic neurotransmitter function and decreased fronto-parietal metabolism are involved in mechanisms of depression in AD and that the metabolic changes are opposite to those observed in late-life major depression.Lower dopamine transporter binding has been associated with decreased initiative, whereas lower cholinergic receptor binding in the left frontal cortex has been reported to be associated with motor and mood changes of apathy .

These findings mirror successful treatment of apathy in AD with the dopaminergic agent methylphenidate (see below). Apathy has been associated with decreased metabolic activity in anterior cingulate and orbitofrontal cortex.

There is growing evidence that apathy in AD is associated with structural atrophy and functional deficits in several medial and inferior frontal regions thought to mediate motivation and reward mechanisms .

Starkstein and colleagues reported that apathy was associated with greater volume of white matter hyperintensities in frontal cortex, suggesting a greater burden of small-vessel ischemic disease. Marshall and colleagues reported that apathy in AD was associated with decreased metabolic activity in anterior cingulated and orbitofrontal cortex.

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