Challenges of memory-sparing medication for Alzheimer’s disease

Alzheimer’s disease is a chronic neurodegenerative brain disorder typically occurring in middle or late life which is characterised by progressive dementia, with three main pathological symptoms: degeneration of acetylcholine cells, accumulation of extracellular plaque, and intracellular neurofibrillary tangles (McKhann et al., 1984). Its global prevalence in people aged 60+ was estimated to be 3.9%, with numbers forecasted to increase by 100% between 2011 and 2040 in developed countries, making it one of the most important health conditions in older people (Ferri et al., 2005).

The cholinergic hypothesis posits that Alzheimer’s disease affects the acetylcholinergic system, resulting in memory loss and degradation of other cognitive functions (Bartus et al, 1982; Cummings & Back, 1998). At present, the standard treatments for Alzheimer’s disease are memory-sparing medications targeting the acetylcholinergic system.

These memory-sparing medications are acetylcholinesterase inhibitors (AChEIs): they block the enzyme acetylcholinesterase (AChE) which breaks down acetylcholine (ACh), thus enhancing the cholinergic transmission by delaying the degradation of acetylcholine in the synaptic cleft (Yiannopoulou & Papageorgiou, 2013). To date, three AChEIss are licensed for the treatment of mild to moderate dementia: donepezil, galantamine, and rivastigmine (Birks, 2006; Farlow, 2002). A fourth medication called memantine is available, which targets the glutaminergic system instead and is indicated as a second-line treatment in moderate to severe Alzheimer’s disease (McShane et al., 2006).

Because the three first-line medications enhance ACh throughout the body as well as the brain, they affect the parasympathetic nervous central system, resulting in gastrointestinal side effects such as nausea, vomiting, and diarrhea; these adverse effects can be so debilitating that they lead to treatment discontinuation (Alva & Cummings, 2008).

Additionally, a population-based cohort study found an association between these memory-sparing medications and increased rates of symptomatic bradycardia (slower than normal heart rate) and syncope (fainting), which according to the study may lead to increased hospital visits, permanent pacemaker insertion, or fall-related injuries, including hip fracture (Gill et al., 2009). The potential for adverse effects is increased by the fact that a typical patient with Alzheimer’s disease is likely to receive concomitant treatments for both related and unrelated conditions (Larco & Jeste, 1994).

Additionally, AChEIs only have a limited impact on behavioural and psychological symptoms of dementia, or BPSD (Birks, 2006; Farlow, 2002), which include four main symptom clusters: psychosis (38% of patients), affective symptoms (59%), hyperactivity (64%) and apathy (65%) (Zec & Burkett, 2008). BPSD are hypothesised to be caused by cell loss in the hippocampus and prefrontal cortex rather than problems in the acetylcholinergic system (Cummings, 2008). Because of this lack of impact on BPSD, clinicians often need to prescribe additional drugs such as SSRIs, SNRIs, and antipsychotic drugs, which may lead to increased risk of adverse events and pose ethical issues (Yiannopoulou & Papageorgiou, 2013).

Perhaps more importantly, and despite modest improvements in cognition, these memory-sparing medications do not prevent or slow down the progression of Alzheimer’s disease (Herrmann et al., 2011), showing limited overall clinical and cost-effectiveness (Loveman et al., 2006). To this day, there is no treatment that prevents the cell loss occurring in Alzheimer’s disease, which is ultimately fatal.

This is because acetylcholine cells loss may not be the primary driver in the progression of the disease (Beatty et al., 1986; Davies, 1999). As a result, current research focuses on the two other pathological symptoms of Alzheimer’s disease: accumulation of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs).

According to the amyloid hypothesis of Alzheimer’s disease, Aβ production in the brain initiates a pathological cascade of events leading to the clinical symptoms of Alzheimer’s disease (Golde, 2005). Aβ, a protein found in the brain which normal function is not well understood (Hiltunen et al, 2009), has a tendency to cluster into oligomers (Haass & Selkoe, 2007). These oligomers eventually form amyloid plaques, which then induce another protein called tau to misfold into intraneuronic tangles (Pulawski et al, 2012), leading to imbalances in various neurotransmitter systems such as acetylcholine, dopamine and serotonin, and to the cognitive deficiencies seen in Alzheimer’s disease (Golde, 2005).

The amyloid hypothesis is promising in terms of developing treatments that are more efficient and more targeted than current memory-sparing medications based on the traditional cholinergic hypothesis of Alzheimer’s disease. These novel treatments could include active immunotherapy – which would aim to interfere with the events in the Aβ-initiated pathological cascade –  but further research is needed before disease-modifying drugs can replace the current symptomatic treatments (van Dyck, 2018).

References:

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McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984). Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS‐ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology34(7), 939-939.

McShane, R., Sastre, A. A., & Minakaran, N. (2006). Memantine for dementia. Cochrane Database of Systematic Reviews, (2).

Pulawski, W., Ghoshdastider, U., Andrisano, V., & Filipek, S. (2012). Ubiquitous amyloids. Applied biochemistry and biotechnology166(7), 1626-1643.

van Dyck, C. H. (2018). Anti-amyloid-β monoclonal antibodies for Alzheimer’s disease: pitfalls and promise. Biological psychiatry83(4), 311-319.

Yiannopoulou, K. G., & Papageorgiou, S. G. (2013). Current and future treatments for Alzheimer’s disease. Therapeutic advances in neurological disorders6(1), 19-33.

Zec, R. F., & Burkett, N. R. (2008). Non-pharmacological and pharmacological treatment of the cognitive and behavioral symptoms of Alzheimer disease. NeuroRehabilitation23(5), 425-438.


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