Editing Cholinergic (section)

== Cholinergic hypothesis of Alzheimer's disease ==
{{Main|Alzheimer's disease}}
{{See also|Cholinesterase inhibitor}}

The hypothesis states that a possible cause of AD is the reduced synthesis of [[acetylcholine]], a neurotransmitter involved in both memory and learning, two important components of AD. Many current drug therapies for AD are centered on the cholinergic hypothesis, although not all have been effective. Studies performed in the 1980s demonstrated significant impairment of cholinergic markers in Alzheimer's patients.<ref>{{cite journal|last=Contestabile|first=A.|title=The history of the cholinergic hypothesis|journal=Behavioural Brain Research| date=August 2011 |volume=221|issue=2|pages=334–340|doi=10.1016/j.bbr.2009.12.044|pmid=20060018|s2cid=8089352 }}</ref>

Thus it was proposed that degeneration of cholinergic neurons in the basal forebrain and the associated loss of cholinergic neurotransmission in the cerebral cortex and other areas contributed significantly to the deterioration in cognitive function seen in patients with Alzheimer's disease<ref>{{cite journal|vauthors=Bartus RT, Dean RL, Beer B|title=The cholinergic hypothesis of geriatric memory dysfunction|journal=Science|date=1982|volume=217|issue=4558|pages=408–417|doi=10.1126/science.7046051|pmid=7046051|bibcode=1982Sci...217..408B }}</ref>

Further studies on the cholinergic system and AD demonstrated acetylcholine plays a role in learning and memory. [[Hyoscine hydrobromide|Scopolamine]], an [[anticholinergic]] drug, was used to block cholinergic activity in young adults and induce memory impairments similar to those present in the elderly. The memory impairments were reversed when treated with [[physostigmine]], a cholinergic agonist. However, reversing memory impairments in AD patients may not be this easy due to permanent changes in brain structure.<ref>{{cite journal|author=Craig, L.A.|author2=Hong, N.S.|author3=McDonald, R.J. |title=Revisiting the cholinergic hypothesis in the development of Alzheimer's disease|journal=Neuroscience & Biobehavioral Reviews| date=May 2011 |volume=35|issue=6|pages=1397–1409|doi=10.1016/j.neubiorev.2011.03.001|pmid=21392524|hdl=10133/3693|s2cid=37584221 |hdl-access=free}}</ref>

When young adults perform memory and attention tasks, brain activation patterns are balanced between the [[frontal lobe|frontal]] and [[occipital lobe]]s, creating a balance between [[Top-down and bottom-up design#Neuroscience and psychology|bottom-up]] and top-down processing. Normal cognitive aging may affect long term and working memory, though the cholinergic system and [[Cerebral cortex|cortical]] areas maintain performance through functional compensation. Adults with AD presenting with dysfunction of the cholinergic system are not able to compensate for long-term and working memory deficits.<ref>{{cite journal|author=Mapstone, M|author2=Dickerson, K|author3=Duffy, CJ |title=Distinct mechanisms of impairment in cognitive ageing and Alzheimer's disease.|journal=Brain|year=2008|volume=131|issue=6|pages=1618–1629|doi=10.1093/brain/awn064|pmid=18385184|doi-access=free}}</ref>

AD is currently treated by increasing acetylcholine concentration by using [[acetylcholinesterase inhibitors]] to inhibit [[acetylcholinesterase]] from breaking down acetylcholine. Current acetylcholinesterase inhibitors approved in the United States by the FDA to treat Alzheimer's include [[donepezil]], [[rivastigmine]], and [[galantamine]]. These drugs work to increase the levels of acetylcholine and subsequently increase the function of neural cells.<ref name="Tabet, N. 2008 336–338">{{cite journal|author=Tabet, N.|title=Acetylcholinesterase inhibitors for Alzheimer's disease: anti-inflammatories in acetylcholine clothing.|journal=Age Ageing| date=July 2008 |volume=35|issue=4|pages=336–338|doi=10.1093/ageing/afl027|pmid=16788077|doi-access=free}}</ref> However, not all treatments based upon the cholinergic hypothesis have been successful in treating the symptoms or slowing the progression of AD.<ref>{{cite journal|author=Martorana, A|author2=Esposito, Z|author3=Koch, G|title=Beyond the Cholinergic Hypothesis: Do Current Drugs Work in Alzheimer's Disease? |journal=CNS Neuroscience & Therapeutics| date=August 2010 |volume=16|issue=4|pages=235–245|doi=10.1111/j.1755-5949.2010.00175.x|pmid=20560995|pmc=6493875}}</ref>  Therefore, a disruption to the cholinergic system has been proposed as a consequence of AD rather than a direct cause.<ref name="Tabet, N. 2008 336–338"/>