The history of attempts to treat Alzheimer's disease is littered with costly failures. One can blame the complexity of both the brain and the condition, which resists attempts to pick apart its contributing mechanisms. One can blame the fact that Alzheimer's is a condition that only naturally occurs in humans (and perhaps dolphins and chimpanzees, with limited evidence in both cases). Access to the biochemistry of the living brain in humans in the ways needed for Alzheimer's research is essentially impossible for ethical and practical reasons. Equally, any practical animal model of Alzheimer's disease, such as the many mouse models, is artificial and embodies certain assumptions about which pathology and processes are most important. Treatments that address the artificially created pathology in the model tend to be successful in that model. Then they fail in humans, after great expense, demonstrating that some of the assumptions were incorrect.
Today's open access review paper is a concise tour of the major categories of drug development. It does omit a range of therapies targeting pathological neurofibrillary tangles made of hyperphosphorylated tau protein, a feature of late stage Alzheimer's disease, and a number of more recent approaches such as clearance of senescent cells as a way to reduce inflammation and tissue dysfunction. Overall it is a cautionary tale for anyone who might be feeling enthused about any of these other approaches to the condition. At some point, the right mechanism will be targeted, but which one is it? The classic problem for every age-related condition is that there is no shortage of contributing mechanisms to consider, but without having already developed a therapy that can address one mechanism in isolation, it is next to impossible to determine whether that one mechanism is important and a good target.
Therapeutic agents for Alzheimer's disease: a critical appraisal
Alzheimer's disease (AD), the most common cause of dementia, is a progressive neurodegenerative disorder, characterized by the degeneration of cholinergic neurons in the nucleus basalis, and the presence of extracellular plaques of beta amyloid (Aβ) and intracellular neurofibrillary tangles composed of phosphorylated tau. AD presents with an impairment in early episodic memory, followed by a gradual and progressive deterioration in cognition and behavior.
The characteristic features of the familial form (FAD) were originally described by Alois Alzheimer in 1906. In FAD, Aβ-containing plaques appear at least 20 years before any signs of memory impairment. While prevention of Aβ formation could provide a treatment option for FAD if started early enough, it represents only about 1% of subjects with AD. The rest have the sporadic form of AD (SAD), with an age of onset of more than 65 years. Their brains also have Aβ-containing plaques, but so do those of healthy, older people with no overt signs of dementia. Since no correlation was found between the number of Aβ plaques and the degree of cognitive impairment in individuals with SAD, the original hypothesis was changed and soluble oligomers of Aβ proposed as the cause of neurodegeneration.
During the last decade, the pharmaceutical industry has concentrated its efforts to affect the processes leading to neurodegeneration by developing drugs to decrease Aβ. Mutations in genes and precursors of Aβ are found in the familial form of the disease. This led to the evaluation of seven monoclonal antibodies against Aβ in subjects with AD, two of which were approved for use by the FDA. They caused only a small improvement in cognitive function, probably because they were given to those with much more prevalent sporadic forms of dementia. They also have potentially serious adverse effects.
γ-secretase is a multi-subunit protease that was identified as responsible for the generation of Aβ, and thus considered a prime therapeutic target in AD. This led to the development of γ-secretase inhibitors like semagacestat to inhibit the formation of Aβ. However, a phase 3 trial in patients with mild to moderate AD was prematurely stopped because the drug actually worsened several measures of cognitive function. Like other γ-secretase inhibitors, avagacestat and tarenflurbil, semagacestat caused serious adverse effects, including cancer, skin related disorders, hypersensitivity reactions, increase in infections, and renal failure. β-secretase inhibitors also prevent formation of Aβ from amyloid precursor protein and their adverse effects are less serious than those of γ-secretase inhibitors. However, verubecestat, atabecestat, and lanabecestat all worsened cognitive function in subjects with mild-moderate AD.
Oxidative stress and elevated pro-inflammatory cytokines are present in all subjects with AD and are well correlated with the degree of memory impairment. Drugs that affect these processes include TNFα blocking antibodies and MAPK p38 inhibitors that reduce cognitive impairment when given for other inflammatory conditions. However, their adverse effects and inability to penetrate the brain preclude their use for dementia. Rosiglitazone is used to treat diabetes, a risk factor for AD, but failed in a clinical trial because it was given to subjects that already had dementia. Ladostigil reduces oxidative stress and suppresses the release of pro-inflammatory cytokines from activated microglia without blocking their effects. Chronic oral administration to aging rats prevented the decline in memory and suppressed overexpression of genes adversely affecting synaptic function in relevant brain regions. In a phase 2 trial, ladostigil reduced the decline in short-term memory and in whole brain and hippocampal volumes in human subjects with mild cognitive impairment and had no more adverse effects than placebo.
View the full article at FightAging
