CME

Exploring the Potential of Novel Mechanisms in the Treatment of Alzheimer's and Huntington's Diseases

Rachelle S. Doody, MD, PhD

Baylor College of Medicine
Houston, Texas

The questions below were submitted by your peers based on a recent CME activity.
The Course Director, Dr. Rachelle S. Doody, provides her answers below.

Question 1: What are your thoughts on the possibility that obstructive sleep apnea may be a cause of Alzheimer's disease?

Question 2: I have just diagnosed a 67-year-old patient with primary progressive aphasia. Is there any treatment? I have heard that cholinesterase inhibitors can lead to some behavior problems.

Question 3: Is Alzheimer’s disease still a diagnosis of exclusion, or are there now reliable signs?

Question 4: Please give your opinion regarding amyloid theory of Alzheimer’s disease. What do you think of the current treatment strategies for Alzheimer’s and Huntington’s diseases?

What are your thoughts on the possibility that obstructive sleep apnea may be a cause of Alzheimer's disease?

Obstructive sleep apnea (OSA) can be associated with cognitive difficulties sufficiently severe to meet the criteria for dementia, but this disorder is clinically and neuropathologically distinct from Alzheimer’s disease. In severe OSA, the patient may experience significant O₂ desaturations with chronic hypoxemia that damage the medial temporal lobes and causes short-term memory loss. Often such patients are chronically sleep-deprived because of frequent nocturnal awakenings and insufficient REM sleep, which leads to inattentiveness on tasks assessing attention and concentration. These cognitive symptoms may improve or reverse with treatment of the sleep apnea (Scheltens P et al. Neurology. 1991;41:155156).

In a different scenario, patients with OSA may also have parasomnias and movement disorders such as restless legs syndrome and REM behavior disorder. When the non-obstructive conditions are dominant, the clinician should consider that the patient may have a Lewy body variant of AD (mixed AD pathology along with cortical and subcortical Lewy bodies) or pure dementia with Lewy bodies (McKeith IG et al. Neurology. 2005;65:1863-1872).

In this scenario, the sleep disorder is a manifestation of the dementing disorder, not the cause. Although there is no evidence that any sleep disorder causes AD, it is always possible for a patient to have both conditions.

I have just diagnosed a 67-year-old patient with primary progressive aphasia. Is there any treatment? I have heard that cholinesterase inhibitors can lead to some behavior problems.

Primary progressive aphasia is a syndromic diagnosis, made on the basis of a certain clinical picture, but it can be caused by more than one neuropathologic process—most commonly non-specific brain changes, AD, or fronto-temporal dementia (FTD) (Mesulam MM. N Engl J Med. 2003;349:1535-1541). Even in the earliest stages, it may be difficult to determine which pathology is most likely. Associated non-verbal memory problems might favor AD, while associated behavioral changes (apathy or disinhibition) might favor FTD. More rarely, associated movement disorders such as alien limb phenomenon might suggest corticobasal degeneration (CBD), a disorder that is probably part of the FTD spectrum (Kertesz A. Neurology. 1994;44:2065-2072).

Treatment should target the suspected underlying neuropathologic process. If AD is suspected, cholinesterase inhibitors and/or memantine may be helpful. There are no FDA-approved treatments for FTD or CBD. Anecdotally, some patients with FTD may become anxious or agitated on cholinesterase inhibitors; so, primary progressive aphasia patients should be observed carefully if started on AD therapies.

Is Alzheimer’s disease still a diagnosis of exclusion, or are there now reliable signs?

Alzheimer’s disease has never really been just a diagnosis of exclusion because a certain clinical picture must be established first, before the other systemic and brain disorders are ruled out. The patient must have an episodic memory disorder with at least one second domain of cognitive impairment (attention, language, visuo-perceptive ability, frontal-executive ability, praxis). The disorder must represent a change from baseline and must be progressive (McKhann G et al. Neurology. 1984;34:939-944).

For research purposes, it may now be possible to identify some AD patients early, relying more on the basis of testing parameters (Dubois B et al. Lancet. 2007p6(8):734-746). The patient must still have an episodic memory disorder, supported by neuroimaging findings (hippocampal atrophy or parieto-temporal hypometabolism on FDG-PET) and/or CSF biomarkers (low abeta and/or elevated tau protein). These criteria are fairly specific for the presence of AD, but they are not sensitive enough for general clinical use (ie, they would likely miss many cases).

Please give your opinion regarding amyloid theory of Alzheimer’s disease. What do you think of the current treatment strategies for Alzheimer’s and Huntington’s diseases?

Amyloid is an undeniable part of the AD story in that amyloid is either overproduced or not effectively cleared in all cases of AD. Of course, this does not mean that it is the only important pathway by which to intervene with therapies, but it is likely that effective anti-amyloid therapies will be helpful in the delay of onset and treatment of AD.

There are numerous other strategies for the treatment of AD—some of which overlap with the strategies for treating other neurodegenerative diseases, such as Huntington’s disease (Doody RS. Alzheimer’s Dementia. 2008.). Strategies based upon risk factors have not proven to be effective (eg, vitamins to lower homocysteine, statins, estrogen, NSAIDs, DHA). Neurotransmitter-based therapies may still yield helpful agents—especially those targeting the serotonergic system, which is also impaired in AD. Anti-tau drugs may be developed to slow or block the development of neurofibrillary tangles, and several drugs that affect cellular or mitochondrial metabolism may prove to have neuroprotective properties.