The most common forms of dementia are Alzheimer’s disease, vascular dementia, and Alzheimer’s and vascular dementia. Alzheimer’s disease typically starts with memory loss and gradually progresses to include multiple cognitive impairments and neuropsychiatric symptoms. Psychological manifestations such as social withdrawal, depression, anxiety, and paranoia are common. Vascular dementia manifests with memory loss and a wide range of cognitive and behavioral abnormalities depending on the affected brain regions. In addition, a variety of other neurodegenerative diseases produce dementia, such as frontotemporal dementia and Parkinson’s disease with dementia. There has been remarkable progress in understanding the pathophysiology of Alzheimer’s disease and other neurodegenerative diseases during the last decade, but treatments based on such growing understanding, ultimately influencing the course of the disease, are still some years in the future. Thus, existing treatments remain palliative.

Briefly, insights derived from rare early-onset familial cases of Alzheimer’s disease due to single mutations appear to be applicable to the far more common sporadic and late-onset forms (although these forms also clearly have genetic modifiers such as the apolipoprotein E locus). The emerging story suggests that oligomeric forms of a peptide fragment called Aβ are highly toxic to neurons. Ultimately, aggregates of Aβ form the amyloid plaques that mark the late stages of the disease. Treatment development is currently focused on blocking the enzymes that liberate Aβ or enhancing its degradation. Such drugs are nearing the stage of clinical trials, but there is not yet evidence of safety and efficacy in humans. Another strategy has been to vaccinate individuals against Aβ; an early trial was suggestive of efficacy but produced serious autoimmune toxicities. New approaches to vaccine strategies are being pursued.

Neuroinflammation and its effects on neurodegeneration have also been explored for possible therapeutics in Alzheimer’s dementia. Tissue necrosis factor-α has been examined because it is known to increase expression of interleukin-1, which subsequently leads to the production of proteins used to form amyloid plaques and neurofibrillary tangles. Therefore, tissue necrosis factor-blockers used in treating arthritis are being investigated for their possible benefit in Alzheimer’s dementia. Indeed, a recent case report found that etanercept, a tissue necrosis factor blocker effective for treating rheumatoid arthritis, proved to markedly improve cognitive test scores when given perispinally over several weeks. Further controlled studies are required, but this may be the start of new treatments focused on the immune system.

The workup for dementia and the differential diagnosis are beyond the scope of this chapter, but workup includes a detailed history, physical examination, and neuropsychiatric testing. Imaging studies may be appropriate based on the findings. At present, imaging to detect early Alzheimer’s disease is still experimental; studies using magnetic resonance imaging measurements of hippocampus or positron emission tomography studies of hippocampal metabolism and other approaches using probes for brain amyloid appear promising, but they are not yet ready for clinical use. Table 8.1 outlines some medical, psychiatric, and drug-induced conditions that are in the differential diagnosis of a person presenting with dementia.

The findings that cholinergic neurons were affected early in the course of Alzheimer’s disease and that acetylcholine plays a critical role in cognitive processes, including memory, resulted in clinical trials of drugs that block acetylcholinesterase, the synaptic enzyme that breaks down acetylcholine. Although the preponderance of agents available for the treatment of Alzheimer’s disease are cholinesterase inhibitors, their clinical effect is modest. Nonetheless, lacking alternatives at present, they are in wide use. Cholinesterase inhibitors that are sufficiently lipophilic to cross the blood-brain barrier can effectively increase the availability of central acetylcholine. Although several well-designed clinical trials have indicated that these cholinesterase inhibitors may be useful in slowing the progression of symptoms, these drugs are at best palliative, provide only modest benefit, and have no known effects on the underlying disease process. Although the cholinesterase inhibitors have been considered a candidate for delaying the onset of dementia, prospective study of patients with mild cognitive impairment find that cholinesterase inhibitors do not delay the onset of dementia. Although cholinesterase inhibitors may not change the course of dementia, they may slow the onset of neuropsychiatric signs and symptoms (e.g., paranoia or agitation) associated with dementia. Unfortunately, patients who stop cholinesterase inhibitors quickly return to the cognitive level of the placebo group. It remains unclear how long the treatment should continue with the cholinesterase inhibitors.

Four cholinesterase inhibitors, tacrine, donepezil, galantamine, and rivastigmine, are currently available for the treatment of cognitive impairment of dementia of the Alzheimer’s type. Because of significant liver toxicity, the first approved agent, tacrine, should not be used. Despite the mild variations in their mechanism of action, the drugs are similar in efficacy. Only tolerability separates them; donepezil is best tolerated.