The focus of Alzheimer’s research has been, so far, the molecular process which leads to a change in the brain structure, above all and first in the hippocampus. Here, an increased formation of amyloid beta (Aß) plaques is observed in the brains of Alzheimer patients. These protein adhesions impair the communication between nerve cells. Such alterations are attributed to ageing and genetic predisposition. Consequently, Alzheimer’s research has been aimed to look for a drug therapy to eliminate or at least contain plaque formation. A very monocausal view of the problem.
There are also studies suggesting that Aß plaque formation cannot be the only problem, once we can find old people, with a high level of plaque formation, who show a very good mental fitness.
Dementia researcher David Snowdon at the University of Minnesota achieved an impressive study that questions plaque formation as a monocausal cause in his so-called nun study, in which a total of 678 nuns aged between 76 and 106 participated.
For several years Snowden was allowed to test their mental abilities and after their death, to examine the brains looking for signs of dementia. The astonishing result: Some brains of nuns who were, until old age, mentally fit, active and present very good memory showed all the signs of severe Alzheimer’s dementia (including Aß plaques): Dementia stage 6 (on the Reisberg scale 1 – 7). But how could that happen?
Furthermore, the pathological features of Alzheimer’s disease (amyloid plaques and neurofibrillary tangles – NFT) can be found many years before the beginning of the symptoms. Such evidences lead to many different researches trying to find a cause to AD other than fate (genetic or ageing).
Viral and bacterial infections have been suspected since the early 20th century to be a possible trigger of dementia. Microglia in the brain of dementia patients were discovered as early as 1919. These cells in the quantities detected there only occur under certain conditions: namely, during inflammation!
Much later, in 2004, Dr. Scott Little and colleagues investigated whether certain bacteria (e.g. chlamydia) could possibly be the cause of Alzheimer’s dementia.
The current research results suggest that even if a brain infection with microorganisms is not the triggering event in the neuropathogenesis that ends with Alzheimer’s disease, but merely an opportunistic spread of the pathogen to an already damaged organ, such infections may well aggravate or accelerate the development of the disease.
These studies suggest that the simple presence of plaques in the brain is not the only cause of AD. The connections must therefore be multi-causal and it is important not to think again in pure repair mechanisms and not to put all energy and money into the medicinal dissolution of plaques, but to question what is going so wrong, causally and systemically, that more and more people obviously fall ill. What makes our body system to be so unbalanced, that the regeneration of the brain areas is no longer possible?
Brain inflammation appears to have a dual function: On one hand it plays a neuroprotective role during an acute-phase response, but on the other hand it becomes detrimental when a chronic response is triggered. Acute inflammation is a well-established defense against infection, toxins, and injury, but when a disruption in the equilibrium of anti-inflammatory and pro-inflammatory signaling occurs, as seen in AD, it results in chronic inflammation.
Microglia are the resident immune cells within the central nervous system (CNS). In a healthy brain, microglia are in an inactive, “resting” state. Any threat to the CNS, such as invasion, injury, or disease, leads to microglial activation with morphological changes and migration to affected areas within the brain. Chronically activated microglia, however, release a variety of proinflammatory and toxic products, including reactive oxygen species, nitric oxide, and cytokines.
In AD, it is hypothesized that the primary driver of activation of microglia is the presence of Aβ.
Activated microglia respond to Aβ resulting in migration to the plaques and induction of phagocytosis (destruction) of Aβ. However, after prolonged periods, these microglia become enlarged and are no longer able to process Aβ. But they are still producing and releasing a great amount of proinflammatory products. This results in an accumulation of Aβ and sustained pro-inflammatory cytokine signaling which begins to damage nerve cells.
Along with microglia, astrocytes and endothelial cells also contribute to inflammatory responses in the brain. While astrocytes are mainly involved in maintaining neuronal function, they are also known to mediate neuroinflammation by receiving and amplifying inflammatory signals from microglia. Amplification of inflammation by astrocytes worsens the neurotoxic environment. This encompasses a self-promoting cycle of inflammation and neuronal death, even after the withdrawal of initial stimuli. This inflammatory mechanism is hypothesized to cause neurodegeneration and set the foundation of neurological disorders such as AD.
In addition to pathological hallmarks, AD is also characterised by abnormal metabolic changes: Our brain is one of the biggest glucose consumers in our body. Not all areas of the brain are dependent on insulin, but especially in the hippocampus, which is the first to be affected by AD, insulin plays a role in glucose uptake. If insulin resistance is present, for example in type 2 diabetes (DM-2), then it can be assumed that the brain also suffers from a partial energy deficiency. As a result, the neural cells are undersupplied. This energetic undersupply can even be detected using imaging methods (PET scan). Alzheimers disease has been often appropriately referred to as type 3 diabetes.
Decreased cerebral glucose metabolism is now considered a distinct characteristic of the AD brain and the association between DM-2 and AD is well established.
Impairments in brain insulin signaling have been found to get progressively worse as AD advances, corresponding to increased levels of amyloid peptides and, in particular, neuroinflammation.
Insulin resistance that arises from DM-2 is proposed to manifest from a prolonged, mild state of inflammation occurring within peripheral tissue. Adipose tissue has been shown to recruit macrophage and stimulate the secretion of numerous proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, which are then easily distributed throughout the rest of the body causing systemic inflammation.
Numerous studies have demonstrated the correlation between peripheral inflammation and cognitive deficits, particularly with mild cognitive impairment (MCI) and AD. Irrespective of the origin of inflammation, proinflammatory cytokines can cross the blood-brain barrier, which triggers brain-specific inflammatory responses. Systemic inflammation is also a primary cause of damage to the blood-brain barrier, allowing entry of peripheral immune cells into the brain.
The mechanism of neuronal insulin resistance appears to be similar with Aβ oligomers inducing microglial activation, which in turn releases numerous pro-inflammatory cytokines. These data are providing evidence for links between molecular pathways and biochemical abnormalities associated with inflammatory mechanisms shared between Alzheimer’s disease and diabetes mellitus.
When the body’s regulatory mechanisms no longer work, we should think in complex systems and ask questions about lifestyle and environmental factors. Why, for example, the factor of inflammation seems to be so relevant, as shown by the research group led by Dr. Pat McGeer (see above)? But if inflammations play a relevant role, shouldn’t we take a look again at inflammation-inducing influences, which are also responsible for basically all chronic diseases? This is very obvious and this approach then leads in the next step to our way of life and our environmental factors, which we can influence.
Stress and sleep play a particularly important role here, as the hippocampus regenerates in healthy sleep cycles and new nerve cells are formed. This “body’s own repair programme” suffers from permanent stress and our stress hormone cortisol in turn stimulates our ß-amyloid, which can then lead to increased plaque formation.
The causes of Alzheimer’s disease are not mono- but multi-causal. The whole person must be in the focus and prevention or therapy must be systemic so that the whole system can adequately heal the person and our self-healing powers (also and above all in our brain) can function again. Epigenetics plays a much more important role here than genetics!
There are two clinical types of Alzheimer’s disease: early-onset and late-onset. Both types have a genetic component.
Early–onset AD occurs before 60 years old and represents less than 10% of all cases. Most cases are caused by dominantly inherited mutations in one of the three genes: β-amyloid precursor protein (APP) – chromosome 21, presenilin 1 (PSEN1) – chromosome 14, and presenilin 2 (PSEN2)-chromosome 1. These genes as well as APOE gene were identified through genetic linkage studies in families. A child whose biological mother or father carries a genetic mutation for early-onset familiar Alzheimer’s disease (FAD) has a 50/50 chance of inheriting that mutation. If the mutation is in fact inherited, the child has a very strong probability of developing early-onset FAD. Each of these mutations plays a role in the breakdown of APP, a protein whose precise function is not yet fully understood. This breakdown is part of a process that generates toxic formsof amyloid plaques.
Late-onset AD is the most common form of the disease, in which symptoms become apparent in the mid-60s and later. The causes of late-onset Alzheimer’s are not yet completely understood, but they likely include a combination of genetic, environmental, and lifestyle factors that affect a person’s risk for developing the disease.
No specific gene directly responsible for the late onset form was found. However, one genetic risk factor—having one form of the apolipoprotein E (APOE) gene on chromosome 19—does increase a person’s risk. APOE comes in several different forms, or alleles:
APOE ε4 is called a risk-factor gene because it increases a person’s risk of developing the disease. However, inheriting an APOE ε4 allele does not mean that a person will definitely develop Alzheimer’s. Some people with an APOE ε4 allele never get the disease, and others who develop Alzheimer’s do not have any APOE ε4 alleles. A blood test can identify which APOE alleles a person has, but results cannot predict who will or will not develop Alzheimer’s disease.
The interaction between genetic and environmental factors and consequently alterations on gene expression are responsible for the development of AD. It is unlikely that genetic testing will ever be able to predict the disease with 100 percent accuracy, researchers believe, because too many other factors may influence its development and progression. Genetic testing is used by researchers conducting clinical trials (they can study a population with higher risk of dementia) and by physicians to help diagnose early-onset Alzheimer’s disease. However, genetic testing is not otherwise recommended.