Attention-Deficit Medications: Potential Use for Alzheimer’s Disease?

A recent systematic review and meta-analysis article published in the July 2022 Journal of Neurology, Neurosurgery and Psychiatry suggests noradrenergic agents may be effective in early Alzheimer’s Disease to improve cognitive function. This original research included over 1800 patients showing a small significant positive effect on the global cognition measured on the Mini-Mental State Exam (MMSE) or on Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog). 

The pathophysiologic theory behind the repurposing of noradrenergic agents is that the neurotransmitter norepinephrine is normally released by the locus coeruleus, and that accumulation of the tau protein found in Alzheimer’s may begin in the locus coeruleus early in Alzheimer’s disease.  The neurotransmission of norepinephrine plays a vital role in attention, memory and executive functioning directly contributing to the applicability to early Alzheimer’s dementia. Furthermore, the proposed mechanism of neuropsychiatric symptoms and behaviors may involve the noradrenergic system and the locus coeruleus.

Many medications target the noradrenergic system by inhibition of norepinephrine reuptake presynaptically, reduced degradation and direct blockade or stimulation of postsynaptic receptors.  Example agents include stimulants such as methylphenidate, atomoxetine and modafinil, some of which are used for attention deficit disorder​​. Years ago, these drugs were studied with minimal effects on Alzheimer’s and interest waned. Now, with identification of the locus coeruleus’ potential involvement and the new tools to assess cognitive function, there is a hypothetical relevance for early Alzheimer’s disease. 

Of the 18 studies included in this meta-analysis, ten studies showed a small but significant improvement in global cognitive function (measured with MMSE and ADAS-cog) with a significant improvement in apathy scores compared to placebo. However, no improvement was seen with neuropsychiatric symptoms, particularly agitation, which may be worsened with noradrenergic agonist medications.

In the SNF setting, these noradrenergic medications have multiple guidelines limiting their use with Beers’ criteria and CMS regulations. Since the use for Alzheimer’s dementia would be off-label, progress notes, adequate monitoring such as liver panel (atomoxetine) and EKG for the stimulants with sufficient references and continued documentation of the effectiveness for each individual patient is of utmost importance. 

In conclusion, these are interesting research findings; however, as practitioners, we need to assess the risks versus benefits of noradrenergic agents, especially cardiovascular risks. In the mildly cognitive impaired patient with early dementia and minimal cardiovascular risk factors, considering a noradrenergic agent for improved apathy and cognitive function might have potential benefit, but more studies are needed to directly address the locus coeruleus involvement and the utility of these agents in the dementia population.

David MCB, Del Giovane M, Liu KY, et al. Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer’s disease: systematic review and meta-analysis. JNeurol Neurosurg Psychiatry 2022;0:1–11. doi:10.1136/jnnp-2022-329136 (open access)

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