Pairing physiology of Alzheimer’s Disease and Lewy Body Dementia with effective drug treatments

From Wikiversity
Jump to navigation Jump to search
Type classification: this is an essay resource.

Pairing physiology of Alzheimer’s Disease and Lewy Body Dementia with effective drug treatments

[edit | edit source]

By 2050, it is estimated that the number of Australians suffering from dementia will be over 730,000, quadruple the figure in the year 2000, with over 175,000 new cases projected annually (Access Economics, 2005). Dementia is the overarching term for the diverse mix of degenerative cognitive and other deficits caused by many underlying conditions (American Psychiatric Association, 2000). These conditions most commonly affect those aged 65 years and over but are not an inevitable consequence of aging (Alzheimer's Australia, 2005). Dementia sufferers require higher levels of care over time, as their cognitive, behavioural and psychological symptoms increasingly affect their daily functioning (Garand, Buckwalter, & Hall, 2000). The widening impact of dementia will fall most personally on those dealing with the diagnosis, their families and carers (Almkvist & Winblad, 1999). It will also place considerable financial and logistical strains on Australia’s health and aged care systems when its tax revenue will reduce due to an aging population (Access Economics, 2005). Substantial research efforts have focussed on pairing the neurophysiology of dementia with effectively targeted drug treatments. Commonly prescribed drugs for two of the most common types of dementia, Alzheimer’s Disease (AD) and Lewy Bodies Dementia (LBD), include cholinesterase inhibitors (ChIs), N-methyl D-Aspartate (NMDA) blockers and neuroleptics (Nagahama, Okina, Suzuki, & Matsuda, 2010; Singh & O'Brien, 2009).

Dementia impacts not only the sufferer, but also their family and carers

AD is a complex mix of cognitive and non-cognitive symptoms which have been associated with the incidence of two brain lesions: amyloid plaques, mainly consisting of amyloid β-peptide; and neurofibrillary tangles (NFTs), comprised primarily of tau proteins (Lahiri & LaFerla, 2006). These brain lesions are believed to progressively damage multiple brain systems, pathways, and associated neurochemical processes, which cause the cognitive and non-cognitive disruptions to functioning (Gsell, Jungkunz, & Riederer, 2004; Lahiri & LaFerla, 2006). For those with mild to moderate AD, the cognitive symptoms include impairment of short and long-term memory, visuospatial and executive functions, and judgement, which worsen over several years as the disease progresses (Frölich et al., 2004). At least half of those with AD also experience behavioural and psychological problems which further impact on their daily functioning (Frölich et al., 2004). These include depression, agitation, psychosis, and disruption to the sleep cycle (Frölich et al., 2004). To more fully understand the physiology of AD and related treatment strategies, it is necessary to explore the nature of the damage disease causes within the brain.

AD causes multiple system impairment, affecting the brain’s ability to produce neurochemicals needed for normal functioning (Almkvist & Winblad, 1999). Gsell and colleagues’ (2004) meta-analysis of the neurochemical impacts of AD encompassed 275 post-mortem studies from 1980 to 1994, with aggregated coverage of 9,535 patients and highlighted functional deficits across most of the brain’s information processing systems. AD caused the brain’s cholinergic system, which is involved in learning and memory processes, to suffer from noticeable and interconnected functional decline (Gsell et al., 2004). This was associated with a reduction in activity of the enzyme cholineacetyltransferase, which synthesises the neurotransmitter acetylcholine, to between 33 and 75% across the limbic, visual, somatosensory and auditory systems (Gsell et al., 2004). Substantial damage also occurred within the nucleus basalis of Meynert, with neuronal loss and depletion of cholinergic enzymes having flow-on effects for complex emotional and motivational behaviour (Gsell et al., 2004). The serotonergic system was also affected, particularly the ventral ascending serotonergic pathway which touches the substantia nigra, caudatus-putamen and the thalamus on its way through the midbrain (Gsell et al., 2004). Decreasing levels of serotonin, which is related to mood, appetite and sleep, were also evident across the limbic and striatal loops (Gsell et al., 2004). The noradrenergic system and dopaminergic system were less clearly impacted (Gsell et al., 2004). However, within the glutamatergic system, transport and uptake systems appeared more involved in the progress of AD than glutamate receptors (Gsell et al., 2004). The uptake system of the major inhibitory neurotransmitter, γ-amino butyric acid, was strongly affected by AD degeneration, particularly in the limbic system and entorhinal cortex (Gsell et al., 2004).

Individual timing and progression of these systemic changes may vary but the NFTs typically begin to appear in the transentorhinal cortex, spreading quickly to the entorhinal cortex and then on to the hippocampus (Thompson et al., 2007). Those brain areas which myelinate later and retain greater plasticity have been found to be more vulnerable to the spread of the disease than those areas, like the primary sensory cortices, which myelinate earlier in infancy (Thompson et al., 2007). After several years, AD spreads further, fully involving the temporal, frontal and parietal lobes (Thompson et al., 2007). Almkvist & Winblad's (1999) review of existing studies showed links between atrophy of the hippocampus and the medial temporal lobes with impairment of episodic memory. Some of the neurophysiological changes associated with AD, such as cholinergic deficits and amyloid plaques have also been found in other dementias, such as LBD; however, there were also some key differences, especially around the progression of the disease (McKeith et al., 2004; Thompson et al., 2007).

Current anti-dementia medication focuses on delaying cognitive degeneration.

Like AD, LBD also damages multiple brain structures and affects the cholinergic system, though to an even greater degree (McKeith et al., 2000). However, in LBD this tends to cause fluctuating cognitive impairments, especially attentional deficits (McKeith et al., 2004). Psychiatric symptoms are also common, usually involving vivid visual hallucinations, misidentifications and delusions (McKeith et al., 2004; Nagahama et al., 2010). Unlike AD, memory deficits develop later in LBD and there is usually less impact on verbal memory than on performance with visuospatial tasks (McKeith et al., 2004). Small scale comparisons of LBD and AD patients showed that those with LBD retained more cortical grey matter in their temporal and orbitofrontal cortices and showed more severe anterior cingulate atrophy (Singh & O'Brien, 2009). This was consistent with earlier studies showing that the increased memory deficits associated with temporal lobe degeneration occurred later in LBD patients (Singh & O'Brien, 2009). Frequently, those with LBD have the same amyloid plaques and NFTs as those with AD (McKeith et al., 2004). LBD also shares physiological features, such as the presence of Lewy bodies, with dementia caused by Parkinson’s Disease (Nagahama et al.2010; McKeith, 2004). However, there has been some evidence to suggest that symptoms of dementia develop much earlier with LBD (McKeith, 2004). The close physiological and symptomatic overlaps of these dementias add complexity to differential diagnoses but also offer potential synergies in terms of the development of drug treatments (McKeith et al., 2004).

Current anti-dementia drugs focus on two main neurochemical systems, the cholinergic and glutamatergic systems, attempting to delay the decline in key neurotransmitters, slowing neuronal loss and the resultant cognitive degeneration (Frölich et al., 2004). ChIs, such as donepezil, rivastigmine and galantamine, target the acetylcholine deficiency associated with memory and learning deficits in AD and LBD by increasing the availability of acetylcholine at the synapse (Frölich et al., 2004). NMDA receptor antagonists, such as memantine, replace the natural NMDA blocker, which no longer functions normally due to disease progression, to maintain glutamatergic neurotransmission which supports learning and memory processes (Frölich et al. 2004; Levin, Batukaeva, Smolentseva, & Amosova, 2009). Both types of drugs do not offer any cure but only address symptoms, potentially helping to prolong quality of life. Therefore, the key questions in relation to drug effectiveness are which patients benefit from the treatment, to what extent, for how long, and at what cost in terms of adverse side effects (Frölich et al., 2004). There have been some mixed reports about the benefits of ChIs although they have been one of the standard treatments for those with mild to moderate AD as well as being used for LBD (Feldman et al., 2009; Simard & van Reekum, 2004; Singh & O'Brien, 2009). Gsell and colleagues (2004) suggested ChIs were beneficial for less than 70% of AD patients, that is, those with mild dementia. However, the most comprehensive systematic review of the use of ChIs for AD to date found otherwise (Birks, 2006). Birks’ (2006) review, which included 13 randomized, placebo controlled double-blind trials conducted over six months or more, found that, at the recommended dosages, there were clinically discernible cognitive improvements for AD patients as well as benefits for day-to-day functioning and behaviour. Although none of the treatment effects were large, a key finding was that treatment benefits were similar for those with mild, moderate or severe AD (Birks, 2006). Birk’s review did point to higher levels of adverse side effects, such as dizziness, nausea, vomiting and insomnia, with ChIs compared to control groups, which may be partially reflected in drop-out rates (29% in the treatment group compared to 18% in the control). However, fewer side effects were associated with donepezil than rivastigmine (Birks, 2006). Reassuringly, Feldman and colleagues' (2009) meta-analytic study of mortality rates from 12 galantamine trials which involved 6,502 patients in treatment groups and 2,368 in placebo control groups, found that mortality rates were no higher than in the control group. While the evidence base for the use of ChIs for LBD has not been as comprehensive, some emerging evidence has shown that LBD responded even better to ChIs, consistent with the greater cholinergic deficits associated with LBD (McKeith et al., 2004). However, a more current and comprehensive systematic review of ChI effectiveness for LBD could strengthen the evidence base.

Reviews of memantine similarly focus on AD rather than LBD. A systematic review of 15 studies (12 of which were on AD but none on LBD) found that memantine offered clinically detectable benefits for patients with moderate to severe AD at a dosage of 20mg/day over 28 weeks compared to a placebo (McShane, Areosa Sastre, & Minakaran, 2006). Disease progression slowed with improvements in cognition, mood and memory, with minimal side effects (McShane et al., 2006). Patients were also less likely to become agitated, which can be a major issue for those in the later stages of AD (McShane et al., 2006). While the effect sizes from the reviewed studies were small, it was argued nevertheless that these were significant improvements in terms of quality of life (McShane et al., 2006). The results of a small scale study suggest that memantine may also provide benefits for LBD patients in terms of cognitive improvement with only mild to moderate side effects (Levin et al., 2009). However, these results need to be replicated more broadly to be convincing.

Drugs have also been used to control the non-cognitive deficits associated with dementia, which include depression, anxiety, agitation and various psychoses, with mixed success (Frölich et al., 2004). For example, psychoactive drugs which target the dopamine system and are normally used to manage psychotic symptoms for mental illnesses, such as schizophrenia, have been prescribed for the psychotic symptoms of dementia (McKeith et al., 2004). However, these have been associated with substantial side effects for limited gains (Frölich et al., 2004). Common sedative effects associated with these drugs counteract efforts to help dementia patients retain sufficient impetus and focus to maintain existing daily functioning (Frölich et al., 2004). They have also been associated with major adverse side effects such as stroke (Frölich et al., 2004). However, for LBD patients, even greater risks have been associated with the use of traditional neuroleptics, such as haloperidol, with severe and adverse sensitivity reactions found in up to 50% of patients and associated with up to a threefold increase in mortality (Ballard, Grace, McKeith, & Holmes, 1998; McKeith et al., 2004). Even with the newer generation of atypical antipsychotic drugs, sparing and judicious use is recommended for LBD as sensitivity has continued to be an issue (McKeith et al., 2004).

Key physiological differences between the diseases which underlie dementia may have important impacts for developing and targeting drug therapies. Correct diagnosis of the dementia type and its severity is critical to the effectiveness of any drug treatment. There has been a significant body of evidence to support the role of ChIs in controlling cognitive symptoms associated with mild to moderate AD (Birks, 2006). There have been early signs that these drugs may be even more effective in counteracting the symptoms of LBD, improving cognitive outcomes (McKeith et al., 2004). For moderate to severe AD and potentially for LBD, NMDA antagonists seem well placed to improve cognition and minimise agitation and enhancing quality of life (McShane et al., 2006). Neuroleptic drugs have been shown to provide some benefits for those with AD but adverse and potentially severe effects compromise their effectiveness (Frölich et al., 2004). Nor have neuroleptics been recommended for LBD because of severe sensitivity issues (Ballard et al., 1998; McKeith et al., 2004). The projected impact of dementia over the next 50 years surely justifies further investment in dementia research. While expensive, studies which use timescales more consistent with the progression of the underlying conditions (years rather than months) would help to provide a more realistic picture of potential treatment benefits (Birks, 2006). Similarly, research which considers any interactions between dementia drugs and other common prescriptions would also be useful (Singh & O'Brien, 2009).


[edit | edit source]
  1. Access Economics. (2005). Dementia estimates and projections: Australian states and territories. Retrieved from
  2. Almkvist, O., & Winblad, B. (1999). Early diagnosis of Alzheimer dementia based on clinical and biological factors. European Archives of Psychiatry & Clinical Neuroscience, 249, S3. Retrieved from
  3. Alzheimer's Australia. (2005). What is dementia? Help Sheet 1.1. Retrieved from
  4. American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed., text revision). Washington, DC: Author.
  5. Ballard, C., Grace, J., McKeith, I., & Holmes, C. (1998). Neuroleptic sensitivity in dementia with Lewy bodies and Alzheimer's disease. Lancet, 351(9108), 1032. doi:10.1016/S0140-6736(05)78999-6
  6. Birks, J. (2006). Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database of Systematic Reviews (Online), (1), CD005593. Retrieved from
  7. Feldman, H. H., Pirttila, T., Dartigues, J. F., Everitt, B., Van Baelen, B., Brashear, ...Kavanagh, S. (2009). Analyses of mortality risk in patients with dementia treated with galantamine. Acta Neurologica Scandinavica, 119, 22-31. doi:10.1111/j.1600-0404.2008.01047.x
  8. Frölich, L., Fox, J., Padberg, F., Maurer, K., Möller, H., & Hampel, H. (2004). Targets of antidementive therapy: Drugs with a specific pharmacological mechanism of action. Current Pharmaceutical Design, 10, 223-229. Retrieved from
  9. Garand, L., Buckwalter, K. C., & Hall, G. R. (2000). The biological basis of behavioral symptoms in dementia. Issues in Mental Health Nursing, 21, 91-107. doi:10.1080/016128400248284
  10. Gsell, W., Jungkunz, G., & Riederer, P. (2004). Functional neurochemistry of Alzheimer's disease. Current Pharmaceutical Design, 10, 265-301. Retrieved from
  11. Lahiri, D. K., & LaFerla, F. M. (2006). Marking the centennial of Alzheimer's first report of the disease with a perspective of ongoing research and future challenge. Current Alzheimer Research, 3, 409-410. doi:10.2174/156720506779025260
  12. Levin, O. S., Batukaeva, L. A., Smolentseva, I. G., & Amosova, N. A. (2009). Efficacy and safety of memantine in Lewy body dementia. Neuroscience and Behavioral Physiology, 39, 597-604. doi:10.1007/s11055-009-9167-x
  13. McKeith, I., Del Ser, T., Spano, P., Emre, M., Wesnes, K., Anand, R., ...Spiegel, R. (2000). Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet, 356(9247), 2031. doi:10.1016/S0140-6736(00)03399-7
  14. McKeith, I., Mintzer, J., Aarsland, D., Burn, D., Chiu, H., Cohen-Mansfield, J., ...Reid, W. (2004). Dementia with Lewy bodies. Lancet Neurology, 3, 19. doi:10.1016/S1474-4422(03)00619-7
  15. McShane, R., Areosa Sastre, A., & Minakaran, N. (2006). Memantine for dementia. Cochrane Database of Systematic Reviews, (2) Retrieved from
  16. Nagahama, Y., Okina, T., Suzuki, N., & Matsuda, M. (2010). Neural correlates of psychotic symptoms in dementia with Lewy bodies. Brain: A Journal of Neurology, 133, 557-567. doi:10.1093/brain/awp295
  17. Simard, M., & van Reekum, R. (2004). The acetylcholinesterase inhibitors for treatment of cognitive and behavioral symptoms in dementia with Lewy bodies. The Journal of Neuropsychiatry and Clinical Neurosciences, 16, 409-425. doi:10.1176/appi.neuropsych.16.4.409
  18. Singh, B., & O'Brien, J. (2009). When should drug treatment be started for people with dementia? Maturitas, 62, 230-234. doi:10.1016/j.maturitas.2008.12.022
  19. Thompson, P. M., Hayashi, K. M., Dutton, R. A., Chiang, M., Leow, A. D., Sowell, E. R., ...Toga, A. W. (2007). Tracking Alzheimer's disease. In H. Federoff (Ed.), Imaging and the aging brain. (pp. 183-214). Malden: Blackwell Publishing. Retrieved from University of Canberra E-Reserve.


[edit | edit source]

The original version of this essay was by Jeanette Hunter and was a prize winner NSW/ACT Dementia Training Student Centre essay competition, 2011.

See also

[edit | edit source]