One ideal way to slow the neurodegenerative processes that give rise to Alzheimer’s Disease (AD) is by applying therapeutic interventions during the preclinical stage of the disease. However, at present identifying patients at high risk of developing AD requires costly and/or invasive procedures to detect specific biomarkers, including through the imaging of neocortical amyloid and tau protein aggregation by positron emission tomography (PET). This procedure is limited both by the facilities with expertise to perform it, and the patients with the resources to participate.
While PET scanning will remain important, the scopolamine challenge test (SCT) may offer another method for understanding early AD related changes in people at risk for the disease. It may also provide a basis for other diagnostic markers of AD related neurodegeneration. In a recent publication in Alzheimer’s Research and Therapy, the authors present a positive outlook around the potential of the SCT to act as an indicator of cognitive change and neocortical amyloid aggregation.
Read the Full Article Here – Disruption of cholinergic neurotransmission, within a cognitive challenge paradigm, is indicative of Aβ-related cognitive impairment in preclinical Alzheimer’s disease after a 27-month delay interval.
In addition to highlighting the opportunity of the SCT to identify AD progression, the paper is important because it shows an integration between models of AD focused on disruption to acetylcholine neurotransmission and those focused on amyloid accumulation. Models of AD that focused on acetylcholine neurotransmission were central to AD research from the 1980s to the early 2000s. These models gave rise to the acetylcholinesterase inhibitors that are now approved for treatment of dementia.
With increased understanding of amyloid and the availability of amyloid biomarkers, models of AD moved their focus to amyloidopathies, and their downstream consequences for tauopathy, neurodegeneration and cognitive loss. This is expressed most clearly in the Jack curves that are now used commonly to show the genesis of AD.
“One thing that had always struck us about the Jack curves is that there is no mention of acetylcholine on that model,” said Paul Maruff, PhD, Chief Science Officer at Cogstate and an author on the paper. “Peter Snyder and I often ask one another about what happened to all the information about disruption to acetylcholine neurotransmission in early AD that was generated from research conducted prior to 2000”
This most recent study—led by Jessica Alber, PhD, University of Rhode Island—is one of a series in which the researchers have sought to integrate models of amyloid and acetylcholine by showing first that in healthy older adults (mean age 62 years), with abnormally high amyloid, determined by PET, that very low doses of the muscarinic antagonist scopolamine (0.2mg), result in a substantial deterioration in memory and executive function, as measured by the Groton Maze Learning Test. In matched older adults whose amyloid levels were within normal limits, the low dose of scopolamine had no effect on cognition.
This study shows that when followed for 27 months after undergoing the initial scopolamine challenge, individuals who had the negative cognitive effect, showed a much greater decline in memory, measured using the International Shopping List Delayed Recall Test (ISLR) compared to those who did not. This indicates that the immediate negative effect to scopolamine provides a good predictive model of decline in episodic memory over the next 27 months. It also shows that disruption to acetylcholine neurotransmission occurs very early in AD, at least before any symptoms are evident. However, this subtle cholinergic loss can be seen clearly with pharmacological challenge.
“The results therefore suggest that the importance of acetylcholine neurotransmission to AD has not been diminished by the amyloid-centric view of the disease,” said Maruff. “Importantly, it also suggests that facilitation of cholinergic neurotransmission may be useful in early AD, at least until vaccines become available, or maybe even on top of any vaccine treatment.”
In short, the paper promotes the intersection of models of disruption to acetylcholine neurotransmission and the amyloid-centric approaches in AD research and suggests that the SCT may be a useful method for determining risk of AD progression and may provide an option for a low-cost, minimally invasive screening method. Authors note that further research in this realm should examine the use of the SCT as a screening measure in regions where Aβ PET imaging is not readily available.