Alzheimer’s disease (AD) is an age-related neurodegenerative disease that is characterized by a progressive loss of memory associated with other cognitive sphere deficits interfering with social and occupational functioning. The global prevalence of AD was estimated at 26.55 million in 2006. During several years preceding the diagnosis of dementia, there is a gradual cognitive decline with a continuum from the predementia stage to the other stages of the disease. Current treatment strategies address impairments of cholinergic and glutamatergic systems. The cholinergic hypothesis was initially presented over 25 years ago and suggests that a dysfunction of acetylcholine containing neurons in the brain contributes substantially to the cognitive decline observed in those with AD. The cholinergic hypothesis of AD states that cholinergic neurons in the basal forebrain are severely affected in the course of the disease, and that the resulting cerebral cholinergic deficit leads to memory loss and other cognitive and non-cognitive symptoms, which are characteristic of the disease. Thus, cholinesterase inhibitors (ChEIs) have long been the cornerstone of treatment for patients with AD. Excessive glutamate levels in the cerebral cortex of AD patients have also been hypothesized to contribute to cognitive deficits in AD. Memantine, a moderate affinity N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, is postulated to counteract this effect. However, the effects of these treatments are limited or controversial and they do not modify disease progression. Currently available evidence strongly supports the position that AD is mainly characterized neuropathologically by the presence of two kinds of protein aggregates: extracellular plaques of Abeta-peptide and intracellular neurofibrillary tangles (NFTs). The initiating event in AD could be related to abnormal processing of ß-amyloid (Aß) peptide, ultimately leading to formation of Aß plaques in the brain. This process occurs while individuals are still cognitively normal. Abeta is a highly aggregatory neurotoxic peptide, derived from the enzymatic cleavage of a membrane protein, the amyloid precursor protein (APP). The 42-residue form of the peptide (Abeta-42) is more prone to aggregation than the shorter and less hydrophobic 40-residue form (Abeta-40). The pathological long term accumulation of toxic oligomeric Abeta assemblies could have a causal role in the onset and progression of the disease. APP is processed by beta and gamma-secretases via the amyloidogenic pathway to produce the toxic variety of Abeta (Abeta-42). The nonamyloidogenic pathway results from alpha-secretase cleavage within the Abeta sequence of APP. According to ABeta peptide cascade hypothesis, ABeta triggers all of the pathological features of the disease, from tau hyperphosphorylation to synaptic dysfunction and neuronal cell death. Even though ABeta has an important role in the AD pathogenesis, different findings speak in favour of a less linear pathophysiology. Patients with sporadic cerebral amyloid angiopathy show great levels of amyloid pathology which is not correlated with cognitive symptoms, and old cognitively normal individuals sometimes exhibit cortical Abeta with almost no tangles. This suggests that amyloid alone is insufficient to explain AD phenotype. Another hypothesis states that Abeta toxicity could be tau dependent or acts in parallel with tau. After a lag period, which varies from patient to patient, neuronal dysfunction and neurodegeneration become the dominant pathological processes. Neurofibrillary tangles are intraneuronal aggregates of paired helical filaments (PHFs) composed of an abnormally hyperphosphorylated intracellular tau protein. Tau normally binds and stabilizes microtubules, the main component of the cellular cytoskeleton. Hyperphosphorylated and aggregated tau lacks its functions and disrupts neuronal transport. It also acts as a toxic stimuli that has an important impact on the viability of neurons: proteolytic cleavage of free tau could generate neurotoxic fragments and abnormal tau sequesters normal tau, MAP1 and MAP2 (other Microtubule-Associated Proteins). In AD, the interaction between deposition of Abeta and hyperphosphorylation of tau is still controversial. Tau could become hyperphosphorylated in response to a disturbance in the balance of physiological kinase/phosphatase activities, which may be initiated by a neurotoxic onset. Abeta and tau could interfere in an original way contributing to a cascade of events leading to the activation of the apoptotic cell death cascade, neuronal death, and transmitter deficits. In the same way, abnormal tau could potentiate Abeta toxicity as disruption of tau processing remains a necessary event in the neurodegenerative cascade and post mortem analyses show that the degree of tau-related pathology correlates much better with the severity of the dementia than does the Abeta burden. Recent advances in understanding AD pathogenesis have led to the development of numerous compounds that might modify the disease process. Investigation for novel therapeutic approaches targeting the presumed underlying pathogenic mechanisms is a major focus of research on AD and it is expected that disease-modifying medications will emerge. Cerebrospinal fluid (CSF) concentrations of Abeta-42 and tau protein could provide good accuracy in discriminating patients with Alzheimer’s disease from control subjects, especially for early stages of the disease. These biomarkers give new possibilities for early clinical trials in AD. This article exposes general classes of potential disease-modifying therapies under clinical investigation for the treatment of AD.
Insuline, glitazones and hormonal therapy
Epidemiologic studies have shown a greater prevalence of AD in patients with type II diabetes. Possible mechanisms through which the risk of cognitive impairment is increased include the effects of peripheral hyperinsulinemia, CNS inflammation, increased formation of advanced glycation end products and regulation of the beta-amyloid peptide. The thiazolidinediones have a potent insulin-sensitising action that appears to be mediated through the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). PPAR-gamma agonists, such as rosiglitazone, also have anti-inflammatory effects. Thiazolidinediones are under evaluation in AD but recent data have shown a potential higher risk of myocardial infarction with these compounds. In order to compensate for the reduced brain’s ability to use glucose in AD, administration of ketone bodies or their metabolic precursors such as medium chain triglycerides
(MCTs) might be another strategy. In a preliminary study with 20 subjects with AD or mild cognitive impairment, single doses of MCTs demonstrated pharmacological activity and significant efficacy in cognitive performance. A phase IIb clinical trial in AD patients confirmed ketone bodies safety and efficacy on cognition. A pivotal, phase III clinical trial in AD patients is planned. Considerable evidence has emerged supporting the neuroprotective effect of estrogens. However, randomized controlled trials suggest a very limited effect of estrogens on attention and verbal performances when administrated to postmenopausal women with AD. The efficacy of selective estrogen receptor modulator (SERMs) that exert tissue-specific estrogenic effects is also investigated in AD randomized controlled trials (table 1). It also appears that estrogens may work in conjunction with Gonadotropins (like luteinizing hormone or LH). LH, which can modulate cognitive behavior, is present in the brain, and has one of the highest receptor levels in the hippocampus. It has been suggested that the increase in Gonadotropin concentrations, following menopause could be one of the causative factors for the development of AD. Reduction in neurodegenerative disease among prostate cancer patients which are frequently treated with Gonadotropin-Releasing Hormone (GnRH) agonist support the role of LH and GnRH in AD. Testosterone supplementation may also benefit cognitive function in men with AD. In healthy older men, short term testosterone administration enhances cognitive function. The potential role of testosterone and its metabolites on cognition requires further research. Among other hormonal compounds, insulin-like growth factor-1 (IGF-1) is supposed to increase clearance of Abeta. Preliminary evidence shows that the growth hormone secretagogue MK-677 (ibutamoren mesylate), a potent inducer of IGF-1 secretion, could improve cognitive function in cognitively impaired patients. However, MK-677 was ineffective at slowing the rate of progression of Alzheimer’s disease in a clinical trial. Excessive levels of corticosteroid have been associated with impaired attention, concentration and memory, and in vivo studies suggest that prolonged exposure to high circulating levels of glucocorticoid may be associated with a faster progression of AD. Mifepristone is a glucocorticoid receptor antagonist and could improve cognition in AD. Pilot trials in patients with AD provide data on the safety and the feasibility of this approach but longer studies are needed.
A. PIAU, F. NOURHASHÉMI, C. HEIN, C. CAILLAUD, B. VELLAS. The Journal of Nutrition, Health & Aging© Volume 15, Number 1, 2011