It can happen slowly. A person's name slips. A stove burner gets left on. Recent and past events become increasingly vague or forgotten. Gradually, memory function, the primary edifice of human meaning and identity built over an individual's lifetime, begins to crumble in response to age-related deterioration of brain function. And the results can be devastating.
Dementia is the most common neurologic disorder affecting the aged population. Alzheimer's disease (AD), the most prevalent form, strikes up to 10% of adults 65 or older, costing society an estimated $100 billion in healthcare costs annually. Fifty percent of those with a family history of AD eventually develop this dementia as they age. [1] As medical science enables more people to live longer, the number of individuals confronting this chronic, disabling degenerative condition threatens to skyrocket. By the year 2040, it is estimated that 14 million Americans will have Alzheimer's.[1] This alarming trend calls for greater preventive strategies to safeguard cognitive health throughout the human lifetime.
In Alzheimer disease, two key structural changes are often observed in the brain:
Like other degenerative processes such as heart disease, these structural changes in the brain appear to be driven by a cluster of interrelated mechanisms, both genetic and environmental, that often precede the clinical diagnosis of AD by decades. Researchers point to "increasing evidence that the previously so-called 'secondary factors' such as a disturbed glucose metabolism, oxidative stress and formation of advanced glycation endproducts (AGEs) and their interaction in a vicious cycle are important for the onset and progression of AD."
Early detection of these measurable physiological processes offers strong clinical guidance for developing effective holistic treatment strategies to defend against the onset and progression of Alzheimer's dementia.
Increased free radical activity (oxidative stress) has been called an "essential factor" fueling Alzheimer's pathology-acting simultaneously as a mediator, product, and trigger for the "clogging" process in the brain and its associated neural damage. Oxidative stress stiffens cell membranes and breaks apart DNA strands in brain neurons -hallmark features of AD-and can accelerate the build-up and clumping of the indigestible beta-amyloid protein that forms plaques.[3]
Brain neurons are easy targets for free radicals because of their low glutathione content, the high proportion of polyunsaturated fatty acids in their cell membranes, and the significant oxygen metabolism taking place in the brain.[3] Neuron membranes damaged by oxidative stress can become depleted of phospholipids, the fatty constituents that provide cell membranes with proper flexibility and permeability. Once phospholipid levels diminish, the cell barrier becomes "dried up" and stiff, no longer able to effectively regulate the flow of nutrients in and out of the cell. As a result, a brain neuron can literally poison itself to death with an overdose of a normally healthy nutrient like calcium.[3]
Alzheimer-damaged brain tissue contains traces of metals such as iron, copper, zinc, and aluminum and patients with AD often exhibit higher concentrations of heavy metals like mercury in both the blood and the brain. Mercury can cause nerve cells to produce a toxic reaction that significantly reduces cellular levels of glutathione, triggering the release of plaque-forming beta-amyloid peptides and the hyper-phosphorylation of tau-protein.[4]
Patients with vascular dementia, Alzheimer's, and poor memory appear more likely to display antioxidant deficiencies in blood plasma, compared with healthy controls.[5-7] In addition, brain tissue of Alzheimer patients often shows deficiencies of powerful free-radical-fighting enzymes such as superoxide dismutase, catalase, and glutathione peroxidase, substances with a marked ability to quench the toxicity of beta-amyloid deposits.[8]
One large-scale study found that antioxidant therapy significantly slowed clinical disease progression in patients with moderate AD, delaying the deterioration of their daily living skills and postponing institutionalization. "No treatment for Alzheimer's disease has shown similar benefits with respect to these outcomes," the investigators concluded.[9]
Dysglycemia appears as a common thread in the pathology of adult-onset type 2 diabetes, cerebrovascular disease, and dementia. Adult-onset diabetics often show poorer cognitive function and experience more rapid cognitive decline during the aging process than healthy controls.[10] In fact, patients with type 2 diabetes have roughly double the risk of developing both vascular dementia and AD.[11]
The well-known destructive impact of diabetes on cerebral blood vessels in the brain is just one possible route in which poor glycemic control may hasten dementia. Diabetes also disrupts insulin signaling to other cells in the body. This altered signaling may increase the activity of a neuronal enzyme that stimulates phosphorylated tau proteins to build up, one of the earliest signs of Alzheimer's.
The accumulation of advanced glycation endproducts (AGEs), deformed proteins generated in response to chronically high blood sugar levels and aging, can also trigger neurodegeneration. Both senile plaques and neurofibrillary tangles contain high amounts of AGEs.[2] AGEs can also activate an acute-phase immune response in the brain's microglial cells, an explosive cascade of inflammatory events that tears apart nearby neurons.
AGEs are closely linked with oxidative stress. Not simply static by-products, glycated proteins generate 50 times more free radicals than non-glycated proteins, increasing the potential of severe damage to nearby neurons.[2] Plaques in the brain consist mainly of proteins bound to transition metals, like copper and iron, which further catalyze the oxidation of AGEs. Oxidative damage to mitochrondria interferes with glucose transport to cells in the brain, preventing neurons from receiving the "fuel" they need-as a result the brain's nerve cells essentially "starve" to death.
It's important to remember that even in the absence of overt diabetes or elevated blood sugar, relative insulin resistance can augment oxidative stress factors.
Amino acids are the building blocks for major brain neurotransmitters and also impact the health and integrity of the vascular system. For this reason, early imbalances may signal important early alterations in the onset of dementia.
Patients with initial symptoms of Alzheimer's exhibit much lower levels of tryptophan and methionine, suggesting disrupted transmethylation already present at this early stage of the disease. Researchers theorize that these imbalances may signal the beginning of disrupted neurotransmission in the brain involving both serotonin and dopamine-which play key roles in regulating sleep, mood, and behavior.[12] Indeed, in patients with AD, tryptophan deficiency has been linked to sleep disorders and poorer mental state/cognitive function.[13,14]
Homocysteine has been cited as an important marker for assessing patients for reversible factors that predispose to both vascular dementia and AD. Investigators from Oxford University report that patients with higher homocysteine levels have a greater than two-fold risk of developing AD.[15] High homocysteine is associated with a more intense clinical progression of the disease, signaled by a more rapid atrophy of the medial temporal lobe and increased microinfarcts, or mini-strokes.
Homocysteine levels often rise in response to deficiencies in B-vitamins. Not surprisingly, levels of folate and vitamin B12 in Alzheimer's patients are often significantly lower than in controls and are closely linked with increased atrophy of the neocortex.[15,16]
Testosterone and estrogen help protect brain neurons from oxidative stress and have been shown to slow the production and prevent the build-up of ß-amyloid plaque.[17,18] 17beta-estradiol, the body's most potent form of estrogen, can stimulate neurons in the hippocampus to generate new synaptic connections with other nerve cells. Estrogen also stimulates blood flow in critical regions of the brain, and helps boost production of important mood-regulating neurotransmitters such as acetylcholine, dopamine, and serotonin.
A recent large-scale study of healthy postmenopausal women found estrogen replacement independently associated with improved cognitive function.[19]
For some women, estrogen replacement therapy may reduce the risk and delay the onset of developing Alzheimer's.[20-22]
Melatonin-a powerful antioxidant and heavy-metal-chelating agent-also shows a marked potential to neutralize the toxic pathology of AD, by boosting antioxidant defense and binding to heavy metals.[4] Melatonin can freely traverse the blood-brain barrier, and is one of the few antioxidants available to all parts of the cell.
DHEA, a sex-hormone precursor that promotes a healthy stress response and decreases with age, shows marked neuroprotective and memory-enhancing effects, with antioxidant properties that may help protect the hippocampus from free radical damage.[23]
But not all hormones are protective. Increasing levels of the stress hormone cortisol, which can creep upward as we age, may also play a detrimental role in dementia.[17] High levels of this adrenal hormone can damage the hippocampus, causing learning impairment and memory loss.[24]
Leading healthcare experts have called the identification of modifiable risk factors for cognitive decline and dementia, such as dysglycemia, "a major health priority." Given the extremely high morbidity and mortality associated with these conditions in our rapidly aging populace, "even relatively small reduction of risk...could have a major public health impact for future generations," they emphasize.[25]
Early preventive treatment to slow or halt the multifactorial process underlying Alzheimer's dementia offers exciting new clinical therapeutic possibilities.
