Alzheimer’s disease?
Why are we doing so little to prevent it?
Donepezil is plainly not the answer, but advances are indicating real protection (Prof David Smith Oxford)
He proved that in cases with high homocysteine levels,B12, folate and B6 showed clear protection.
I hope you can read the following!
Alzheimer’s disease is a physical disease which attacks the brain resulting in impaired memory, thinking and behaviour. The disease is named for the German physician, Alois Alzheimer who, in 1907, first described it.
As brain cells die, the substance of the brain shrinks. Abnormal material builds up as “tangles” in the centre of the brain cells and “plaques” outside the brain cells, disrupting messages within the brain, damaging connections between brain cells. This leads to the eventual death of the brain cells and prevents the recall of information.
Memory of recent events is the first to be affected, but as the disease progresses, long-term memory is also lost. The disease also affects many of the brain’s other functions and consequently, many other aspects of behaviour are disturbed.
There are two different types of Alzheimer’s disease:
Sporadic Alzheimer’s disease
# The disease can affect adults at any age, but usually occurs after age 65
# Sporadic Alzheimer’s disease is by far the most common form of Alzheimer’s disease
# It affects people who may or may not have a family history of the disease. Several competing hypotheses exist trying to explain the cause of the disease.
The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective.
Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid, leading to generalised neuroinflammation.
In 1991, the amyloid hypothesis postulated that amyloid beta (A?) deposits are the fundamental cause of the disease.
Support for this postulate comes from the location of the gene for the amyloid beta precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit AD by 40 years of age.
Also APOE4, the major genetic risk factor for AD, leads to excess amyloid buildup in the brain before AD symptoms arise. Thus, A? deposition precedes clinical AD.
Further evidence comes from the finding that transgenic mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer’s-like brain pathology with spatial learning deficits.
An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia. Researchers have been led to suspect non-plaque A? oligomers (aggregates of many monomers) as the primary pathogenic form of A?. These toxic oligomers, also referred to as amyloid-derived diffusible ligands (ADDLs), bind to a surface receptor on neurons and change the structure of the synapse, thereby disrupting neuronal communication.
One receptor for A? oligomers may be the prion protein, the same protein that has been linked to mad cow disease and the related human condition, Creutzfeldt-Jakob disease, thus potentially linking the underlying mechanism of these neurodegenerative disorders with that of Alzheimer’s disease.
In 2009, this theory was updated, suggesting that a close relative of the beta-amyloid protein, and not necessarily the beta-amyloid itself, may be a major culprit in the disease. The theory holds that an amyloid-related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be triggered by aging-related processes in later life to cause the neuronal withering of Alzheimer’s disease.
N-APP, a fragment of APP from the peptide’s N-terminus, is adjacent to beta-amyloid and is cleaved from APP by one of the same enzymes. N-APP triggers the self-destruct pathway by binding to a neuronal receptor called death receptor 6 (DR6, also known as TNFRSF21).
DR6 is highly expressed in the human brain regions most affected by Alzheimer’s, so it is possible that the N-APP/DR6 pathway might be hijacked in the aging brain to cause damage. In this model, beta-amyloid plays a complementary role, by depressing synaptic function.
A 2004 study found that deposition of amyloid plaques does not correlate well with neuron loss.
This observation supports the tau hypothesis, the idea that tau protein abnormalities initiate the disease cascade.
In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies.
When this occurs, the microtubules disintegrate, collapsing the neuron’s transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells. Herpes simplex virus type 1 has also been proposed to play a causative role in people carrying the susceptible versions of the apoE gene.
Another hypothesis asserts that the disease may be caused by age-related myelin breakdown in the brain. Demyelination leads to axonal transport disruptions, leading to loss of neurons that become stale. Iron released during myelin breakdown is hypothesized to cause further damage. Homeostatic myelin repair processes contribute to the development of proteinaceous deposits such as amyloid-beta and tau.
Oxidative stress is a significant cause in the formation of the pathology.
AD individuals show 70% loss of locus coeruleus cells that provide norepinephrine (in addition to its neurotransmitter role) that locally diffuses from “varicosities” as an endogenous antiinflammatory agent in the microenvironment around the neurons, glial cells, and blood vessels in the neocortex and hippocampus.]
It has been shown that norepinephrine stimulates mouse microglia to suppress A?-induced production of cytokines and their phagocytosis of A?.[54] This suggests that degeneration of the locus ceruleus might be responsible for increased A? deposition in AD brains.
Pathophysiology
Main article: Biochemistry of Alzheimer’s disease
Histopathologic image of senile plaques seen in the cerebral cortex of a person with Alzheimer’s disease of presenile onset. Silver impregnation.
Neuropathology
Alzheimer’s disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus. Studies using MRI and PET have documented reductions in the size of specific brain regions in patients as they progressed from mild cognitive impairment to Alzheimer’s disease, and in comparison with similar images from healthy older adults.
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD. Plaques are dense, mostly insoluble deposits of amyloid-beta peptide and cellular material outside and around neurons. Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves. Although many older individuals develop some plaques and tangles as a consequence of aging, the brains of AD patients have a greater number of them in specific brain regions such as the temporal lobe.[56] Lewy bodies are not rare in AD patient’s brains.
Biochemistry
Enzymes act on the APP (amyloid precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the formation of senile plaques in AD.
Alzheimer’s disease has been identified as a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded A-beta and tau proteins in the brain. Plaques are made up of small peptides, 39–43 amino acids in length, called beta-amyloid (also written as A-beta or A?).
Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron’s membrane. APP is critical to neuron growth, survival and post-injury repair. In Alzheimer’s disease, an unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis. One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaques.
In Alzheimer’s disease, changes in tau protein lead to the disintegration of microtubules in brain cells.
AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilizes the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron’s transport system.
Disease mechanism
Exactly how disturbances of production and aggregation of the beta amyloid peptide gives rise to the pathology of AD is not known. The amyloid hypothesis traditionally points to the accumulation of beta amyloid peptides as the central event triggering neuron degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell’s calcium ion homeostasis, induces programmed cell death (apoptosis). It is also known that A? selectively builds up in the mitochondria in the cells of Alzheimer’s-affected brains, and it also inhibits certain enzyme functions and the utilisation of glucose by neurons.
Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer’s disease. Inflammation is a general marker of tissue damage in any disease, and may be either secondary to tissue damage in AD or a marker of an immunological response.[67]
Alterations in the distribution of different neurotrophic factors and in the expression of their receptors such as the brain derived neurotrophic factor (BDNF) have been described in AD.
Note that BDNF increases with physical exercise.
Genetics
The vast majority of cases of Alzheimer’s disease are sporadic, meaning that they are not genetically inherited although some genes may act as risk factors. On the other hand, around 0.1% of the cases are familial forms of autosomal-dominant inheritance, which usually have an onset before age 65.
Most of autosomal dominant familial AD can be attributed to mutations in one of three genes: amyloid precursor protein (APP) and presenilins 1 and 2.
Most mutations in the APP and presenilin genes increase the production of a small protein called A?42, which is the main component of senile plaques.
Some of the mutations merely alter the ratio between A?42 and the other major forms—e.g., A?40—without increasing A?42 levels. This suggests that presenilin mutations can cause disease even if they lower the total amount of A? produced and may point to other roles of presenilin or a role for alterations in the function of APP and/or its fragments other than A?.
Most cases of Alzheimer’s disease do not exhibit autosomal-dominant inheritance and are termed sporadic AD. Nevertheless genetic differences may act as risk factors.
The best known genetic risk factor is the inheritance of the ?4 allele of the apolipoprotein E (APOE). Between 40 and 80% of patients with AD possess at least one apoE4 allele. The APOE4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes. Geneticists agree that numerous other genes also act as risk factors or have protective effects that influence the development of late onset Alzheimer’s disease. Over 400 genes have been tested for association with late-onset sporadic AD, most with null results.
Apolipoprotein E, type ?4 allele (APOE ?4), is associated with late-onset familial Alzheimer’s disease (AD). There is high avidity and specific binding of amyloid ?-peptide with the protein ApoE. To test the hypothesis that late-onset familial AD may represent the clustering of sporadic AD in families large enough to be studied, we extended the analyses of APOE alleles to several series of sporadic AD patients. APOE ?4 is significantly associated with a series of probable sporadic AD patients (0.36 ± 0.042, AD, versus 0.16 ± 0.027, controls [allele frequency estimate ± standard error], p = 0.00031). Spouse controls did not differ from CEPH grandparent controls from the Centre d’Etude du Polymorphisme Humain (CEPH) or from literature controls. A large combined series of autopsy-documented sporadic AD patients also demonstrated highly significant association with the APOE ?4 allele (0.40 ± 0.026, p ? 0.00001). These data support the involvement of ApoE ?4 in the pathogenesis of late-onset familial and sporadic AD. ApoE isoforms may play an important role in the metabolism of ?-peptide, and APOE ?4 may operate as a susceptibility gene (risk factor) for the clinical expression of AD.
MAJOR PROTECTIVE STRATEGIES
Reverse risk factors for vascular disease.
CORRECT nutritional deficiencies.
(1) Optimize minerals , making sure that copper is not high and that there is no excess of lead, mercury or heavy metals.
(2) Bring B12 to at least 700 pmol/l, folic acid to at least 35 nmol/L, homocysteine to 8umol/L or less.
(3) Optimize vitamin 25D3 to at least 80 nmol/L
(4) Reverse insulin resistance (insulin at 1 hour after meal should be less than 40mU/L, while normalizing glucose and triglycerides, but not over-lowering LDL cholesterol.
(5) Consume sufficient branch chain amino acids (eggs and whey protein)
(6) Omega 3 fatty acids at more than 10ml/day.
ADD PROTECTIVE PLANT SUBSTANCES
(1) Turmeric at one and a half teaspoons twice per day (with black pepper to enhance absorption and prolong half life)(or curcumin 200mg tds with about 20 mg piperine per dose)
(2) Resveratrol 200mg bd
(3) Coenzyme Q10 150 mg daily (as mixed ubiquinone and ubiquinol)
The piperine above will enhance Q10 absorption.
(4) R alpha lipoic acid 100mg tds
(5) Acetyl l-carnitine 500mg bd
(6) Antioxidants, especially berry plants,(anthocyanosides and proanthocyanidins) and dark green vegetables (lutein, zexanthin,vitamin K)
(7) Cocoa flavanoids
(8) Include more raw and fresh food, including plenty of vitamin C.
PREVENT GLYCATION AND CARBONYLATION OF PROTEINS,
Control Glucose levels and use l-carnosine.
ADD PHYSICAL EXERCISE AT LEAST 20 MINUTES TWICE DAILY!
Do mind activities to increase mental diversity.)(Crosswords, sudoku, quizzes etc)
Meditate
Listen to good music every day.
Engage in conversation with interesting people