Alzheimer's DiseaseLife Extension Suggestions
Theories of Alzheimer's Disease
Research into the potential causes of Alzheimer’s disease has been frustrating. A number of processes are believed to contribute to the cognitive decline observed in Alzheimer’s disease. Brain deterioration in Alzheimer’s disease is thought to begin decades before symptoms become evident. Outlined below are several factors postulated to contribute to Alzheimer’s disease; each also represents a potential therapeutic target (Luan 2012; Teng 2012).
A prominent finding in Alzheimer’s disease is that senile plaques, which are comprised of “clumps” of the protein fragment amyloid beta, accumulate and cause cellular damage in key areas of the brain, especially the hippocampus, which is involved in memory consolidation and spatial navigation (Biasutti 2012). Aggregates of amyloid beta have been shown to contribute to oxidative damage, excitotoxicity, inflammation, cell death, and formation of neurofibrillary tangles (NFTs) (see below) (Massoud 2010). However, therapies aimed solely at reducing amyloid beta have proven disappointing, suggesting a more complex process is involved (Marchesi 2012; Schmitz 2004; Holmes 2008).
Neurons contain a cellular skeleton made up of microtubules, secured in place by specialized proteins called tau. In Alzheimer’s disease, microtubules disintegrate and tau proteins “clump” together to form aggregates called neurofibrillary tangles or NFTs. NFTs function much the same as amyloid beta aggregates in that they initiate several process that lead to cellular dysfunction and death. Whether amyloid beta or NFTs arise first in Alzheimer’s disease is unclear, and this remains a heavily debated topic within the scientific community (Massoud 2010; Crespo-Biel 2012).
A theory once widely advocated, but which has proved to be disappointing at addressing underlying disease progression, is the cholinergic hypothesis. This view suggests that Alzheimer’s disease is the consequence of insufficient synthesis of the neurotransmitter acetylcholine, which is fundamental in many aspects of cognition (Munoz-torrero 2008; Nieoullon 2010).
Clinical trials have shown medications that support acetylcholine signaling reduce symptoms, but do not reverse or halt the disease. Therefore, inadequate cholinergic neurotransmission is now viewed as a consequence of generalized brain deterioration observed in Alzheimer’s disease, rather than a direct cause. Nonetheless, drugs that modulate acetylcholine signaling are still a mainstay of symptomatic management of Alzheimer’s disease (Munoz-torrero 2008; Nieoullon 2010).
Oxidative stress is a process in which highly reactive molecules called free radicals damage cellular structures. Free radicals are byproducts of normal metabolism, but during states of metabolic abnormality such as mitochondrial dysfunction (see below), they are created more rapidly and in greater quantity. In the case of Alzheimer’s disease, oxidative stress both facilitates some of the damage caused by amyloid beta and spurs its formation (Dong-gyu 2010; Hampel 2011).
Oxidative stress propagates Alzheimer’s disease via another route as well. As neurons become damaged, free iron accumulates on their surfaces and within nearby cells called microglia. Free iron causes radical formation and drives oxidative stress (Mandel 2006).
The inflammatory process appears to play an important role in the development of Alzheimer's disease (AD). When high levels of amyloid beta accumulate in the brain, it activates the body’s immune response, resulting in inflammation that damages neurons (Salminen 2009). Part of the inflammatory response to amyloid beta appears to be facilitated by tumor necrosis factor-alpha (TNF-α) (Tobinick 2008a). TNF-α is a pro-inflammatory cytokine that is often found in high levels in serum and cerebral spinal fluid (CSF) of Alzheimer’s patients; it represents a potential target for novel Alzheimer’s disease therapies (Culpan 2011; Ardebili 2011; Tobinick 2008a).
Mitochondria are the energy power plants of cells; they generate energy in the form of adenosine triphosphate (ATP), which is necessary for cellular function. Mitochondrial dysfunction has been implicated in many age-related diseases, including Alzheimer’s disease (Chen 2011). One line of evidence that supports a link between Alzheimer’s disease and mitochondrial dysfunction is the finding that ApoE4, a genetic variant associated with Alzheimer’s disease and amyloid beta deposition within the brain, seems to play a role in disrupting mitochondrial respiratory chain function (Caselli 2012; Chen 2011; Polvikoski 1995).
Dysfunctional mitochondria are important mediators of amyloid beta toxicity (Leuner 2012). Mitochondrial dysfunction contributes to an increased burden of oxidative stress as well, which itself is another mediator of amyloid beta toxicity. Mitochondrial dysfunction and oxidative stress then drive the formation of additional amyloid beta, creating a vicious, self-propagating cycle that ultimately leads to neuron death (Leuner 2012).
Glutamate is the most abundant excitatory neurotransmitter in the brain and is necessary for normal brain function. However, too much glutamatergic neurotransmission can be toxic to neurons, a phenomenon known as “excitotoxicity”. Excitotoxicity is thought to contribute to neuronal degeneration in Alzheimer’s disease because it is promoted by amyloid beta, neurofibrillary tangles, mitochondrial dysfunction, and oxidative stress among other factors (Danysz 2012).
Glutamate excitotoxicity is the result of over activation of N-methyl-D-aspartate (NMDA) receptors. Therefore, modulating this receptor is a way to lessen some of the damaging effects of excess glutamate signaling. The FDA has approved memantine (e.g., Namenda®), an NMDA receptor blocker, for the treatment of moderate to severe Alzheimer’s disease (Danysz 2012).
Loss of Sex Hormones
Evidence suggests that age-related loss of sex hormones – estrogen in women and testosterone in men – may contribute to Alzheimer’s disease. Although the specific mechanisms are unclear, sex hormones appear to protect the brain against the development of Alzheimer’s disease (Vest 2012; Barron 2012). For example, declining estrogen and testosterone levels seem to be associated with increased amyloid beta and tau abnormalities (Overk 2012).
An intriguing theory that remains largely unappreciated by the medical community is that chronic infection with a variety of pathogenic bacteria and/ or viruses may contribute to the development of Alzheimer’s disease. Research indicates that some common pathogens are consistently detected in the brains of Alzheimer’s patients. For example, a comprehensive analysis of studies found that Spirochetes, a family of bacteria, was detected in about 90% of Alzheimer’s patients and was virtually absent in healthy age-matched controls. Further statistical evaluation revealed a high probability of a causal relationship between Spirochetes infection and Alzheimer’s disease (Miklossy 2011).
Spirochetes and other bacteria can linger in the brain and drive inflammation and the formation of amyloid beta and neurofibrillary tangles, all of which are hallmarks of Alzheimer’s disease (Miklossy 2011). Moreover, laboratory studies indicate that amyloid beta is an antimicrobial peptide, suggesting its formation could be an adaptive response to infectious organisms (Soscia 2010). These and other findings have led some researchers to hypothesize that “…early intervention against infection may delay or even prevent the future development of [Alzheimer’s disease]” (Honjo 2009).