Samuel Gershon: The Tacrine paradigm

Hector Warnes’ response to Samuel Gershon’s reply

        Alzheimer's disease (AD) is considered to be a multifactorial brain deterioration with loss of memory, cognitive dysfunction and ultimately inability for self-care and self-sufficiency. The early onset AD is about  10% of cases found in those  who inherit an allele of the apolipoprotein E (APOE) gene on chromosome 19. However, patients  with this risk factor may have the gene but do not develop AD. Most of these patients are aged above 60-70, with and increase of  the incidence every decade, 80 or 90  (late-onset), with other risk factors such as vascular disease (leukoaraiosis), obesity, diabetes, inflammatory disease. The characteristic findings on autopsy are amyloid plaques and neurofibrillary or tau tangles that result in loss of neurons and atrophy of the cerebral cortex.

        In younger cases, AD has been found in four genes responsible for the neuroanatomical findings: presenilin1 and 2, amyloid precursor protein gene and the apolipoprotein E genes. So far, every treatment is only symptomatic not etiological. There is no doubt that acetylcholine is one of the principal neurotransmitters in the brain. There is a well-known study on the comparative safety and effectiveness of cholinesterase inhibitors for AD (Li, Shang Y, Zhang and Zhao 2019). It consists of a review of 41 randomized controlled trials since 2017. The authors came to the conclusion that the Rivastigmine 15 cm2 patch was among the better options both in function and global changes. The only sad conclusion is that treatment may only delay by a few years the cognitive decline; it did not act on the neuropsychiatric symptoms (such as insomnia, depression or psychotic agitation).

        One risk factor for Alzheimer's disease is a deficit of cholinergic neurotransmission resulting in a loss of acetylcholine, a neurotransmitter, which stimulates nicotinic and muscarinic receptors in the brain  (Arendt, Bigl, Arendt and Tennstedt 1983). The nucleus basalis magnocellularis or nucleus of Meynert is located in the orbital-frontal brain and its axons  spread over the cerebral cortex. In the study, 58 cases were compared with 14 controls and it was found that a loss of cholinergic neurons occurred in 70 % of Alzheimer's patients, in 77% in paralysis agitans and 47% in Korsakoff's disease (which is related to chronic alcoholism). The authors conclude that the degeneration of these cholinergic centers provide the morphological  correlate of the cholinergic deficiency and are probably related to the progressive deterioration of memory and cognitive processes.

        I totally agree with these findings. There are countless research papers on the subject published by neurologists or neuroscientists. Nancy Andreasen with others published on the results of clinical trials in the Journal of Internal Medicine (Schneider, Mangialasche, Andreasen et al. 2014).  

References:

Arendt T, Bigl V, Arendt A, Tennstedt A. Loss of neurons in the nucleus basalis of Meynert in Alzheimer's disease, paralysis agitans and Korsakoff's disease. Acta Neuropathol 1983;61(2):101-8.

Li DD, Shang YH, Zhang W, Zhao P. Meta-analysis of Randomized Controlled Trials on the efficacy and safety of Donepezil, Galantamine, Rivastigmine and Memantine for the treatment of Alzheimer´s disease. Front Neurosci 2019;13:472.

Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, Mantua V, Mecocci P, Pani L, Winblad B, Kivipelto M. Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014. J Intern Med. 2014;275(3):251-83.

July 1, 2021