Neuropathology

AD has distinctive neuropathologic features, including the following¹:

These findings are particularly evident in the cerebral cortex and hippocampal formation.

The clinical features of AD are believed to be related to cholinergic dysfunction due to appreciable reductions in the activity of the enzyme choline acetyltransferase, the enzyme that synthesizes acetylcholine, and the neuronal transfer of choline.

Etiology

The two core pathologic hallmarks of AD are an accumulation of β-amyloid and the formation of neurofibrillary tangles. Amyloid is a general term for protein fragments that the body produces normally. Beta-amyloid is a fragment snipped from an amyloid precursor protein (APP). In a healthy brain, these fragments are broken down and eliminated. In AD, Beta-amyloid protein fragments accumulate to form hard plaques between neurons, blocking the transmission of messages and leading to the death of brain cells, neurofibrillary tangles, and ultimately, dementia. Tau, a microtubule-associated protein, is the major constituent of neurofibrillary tangles and is produced in soluble hyperphosphorylated form when β-amyloid levels become toxic.

Genetic factors play a major role and are estimated to account for up to 70% of cases of AD. Several genes have been linked to AD: the APP on chromosome 21 (explaining the close association between Down syndrome and AD); the presenilin genes on chromosomes 14 and 1; and the apolipoprotein E (ApoE) gene on chromosome 19. The first two mutations are rare and associated with symptoms developing before the age of 50. The most significant genetic finding is the link with the ApoE gene. One form of ApoE, the e4-type, is linked to a significantly greater risk for AD; another, the e2-type, is associated with significant protection.

Literature is also accumulating regarding the role of genetically linked aberrant immune system regulation of inflammation as a possible contributor to AD. Although innate immune function in the brain is normally modulated to remove plaque in an attempt to maintain health, research is beginning to characterize a chronic and excessive reaction to immune protofibrils of amyloid proteins in the brain that can promote disease.² As a result, immunotherapeutic approaches have recently been developed for the treatment of AD. Chief among these strategies is to immunize AD patients with Abeta peptides so that they will generate antibodies that bind to Abeta protein and enhance its clearance.³ Although preclinical studies were successful, the initial human clinical trial of an active Abeta vaccine was halted owing to the development of meningoencephalitis in approximately 6% of the vaccinated AD patients.

Although genes play a significant role in determining susceptibility to AD, lifestyle and environmental factors also play significant roles, as in most chronic degenerative diseases. Emerging research reveals that dietary factors are important. Poor-quality diets with excess saturated or trans fatty acids may predispose neurons to environmental toxicities.^4,5 Some data suggest that abnormal sleep-wake cycles and decreased morning light exposure may play a role in the expression of AD (see “Melatonin, later”). Traumatic injury to the head; chronic exposure to aluminum, silicon, or both; exposure to neurotoxins from environmental sources; and free radical damage have all been implicated as causative factors as well. As in the pathophysiology of other chronic degenerative diseases, there is considerable evidence that increased oxidative damage plays a central role. Therapies designed to support antioxidant mechanisms (discussed later) may be quite helpful in the prevention of AD.⁶

The tremendous increase in AD parallels the rise in type 2 diabetes and insulin resistance, suggesting a possible connection. It is well established that individuals with type 2 diabetes have a 1.5- to 4-fold higher than normal risk for AD as well as vascular dementia. Impaired insulin signaling and insulin resistance in the brain or the decrease in cerebral insulin receptors associated with aging may be another important factor in the pathogenesis of AD. Furthermore, hyperglycemia induces increased peripheral utilization of insulin, resulting in reduced insulin transport into the brain. Insufficient insulin signaling make neurons energy-deficient and vulnerable to oxidizing or other metabolic insults, leading to the destruction of mitochondria and ultimately the neuron. Cerebral hypoinsulinemia (as well as hyperinsulinemia) leads to β-amyloid accumulation and increased tau phosphorylation. Measures to improve glycemic control and improve both peripheral and brain insulin sensitivity appear to be important steps in the prevention of AD.^7,8

Aluminum

Considerable attention has focused on the association of aluminum concentration in the neurofibrillary tangle (NFT). Whether the aluminum concentration develops in response to AD or whether it initiates the lesions has not yet been determined, but significant evidence shows that it contributes, possibly significantly, to the disease.

Aluminum has a strong affinity for the paired helical filament tau (PHF-t), which is involved in the formation of the NFTs. In fact, studies have demonstrated that aluminum is the cofactor along with this tau filament in the formation of the NFTs.⁹ The aluminum selectively binds to PHF-t, induces PHF-t to aggregate, and retards the brain’s ability to break down PHF-t. Aluminum’s role in AD is further supported by a recent animal study that evaluated long-term exposure to ecologic doses of aluminum. In this study, researchers found ghost-like neurons with cytoplasmic and nuclear vacuolations together with aluminum deposits. The hippocampus contained neuritic plaques while the cerebrovasculature exhibited amyloid deposits. The authors also found behavioral changes in these rats reminiscent of those observed in AD.¹⁰

A great deal of circumstantial evidence links chronic aluminum exposure to AD. Increasing aluminum concentrations in the brain could explain why AD increases with increasing age. A study of 356 healthy people has shown that serum aluminum concentration increases as people age.¹¹ Those with AD have significantly higher aluminum levels than both normal people and patients with other types of dementias, such as those due to alcohol, atherosclerosis, and stroke. Efforts to remove the aluminum appear to help somewhat, but such measures are probably too late once the disease is well established. For example, intramuscular injections of deferoxamine (a chelating agent for the removal of iron and aluminum) over a 2-year period showed a significant slowing of the rate of decline in 48 AD patients.¹²

Even in those without mental disease, elevated aluminum levels are associated with poorer mental function. For example, in a study of dialysis patients, the 13 patients who had a positive aluminum deferoxamine test (a measure of the amount of aluminum in the body) were compared with 13 who had a negative test. Subjecting the entire group to four attention tests and two memory tests revealed that those with higher levels of aluminum had a moderate to considerable disturbance of mental function.¹²

The aluminum appears to come from the water supply, food, antacids, and deodorants. The most significant source is probably drinking water, because the aluminum in water is in a more bioavailable and thus potentially toxic form. Researchers measured the aluminum absorption of tap water by adding a small amount of soluble aluminum in a radioactive form to the stomachs of animals. They discovered that the trace amounts of aluminum from this single exposure immediately entered the animals’ brain tissue. The frightening news is that aluminum in water occurs not only naturally but is also added (in the form of alum) to treat some water supplies.¹³

Fingerprint Patterns

Abnormal fingerprint patterns are associated with both AD and Down syndrome.¹⁵ Compared with the normal population, AD and Down syndrome patients show an increased number of ulnar loops on the fingertips, with a concomitant decrease in whorls, radial loops, and arches. Ulnar loops (pointing toward the ulnar bone, away from the thumb) are frequently found on all 10 fingertips. Radial loops (pointing toward the thumb), when they do appear, tend to be shifted away from the index and middle fingers—where they most commonly occur—to the ring and little fingers. In patients with this fingerprint pattern, which is characteristic of AD, it is recommended that an aggressive preventive approach be instituted immediately.

Diet

Dietary factors are clearly important in the etiology of AD. Food choices consistent with the standard American diet are associated with a significant risk for the development of AD. A diet high in saturated fat and trans fatty acids and low in dietary antioxidants may lead to increased serum and brain concentrations of aluminum and transition metal ions, which are implicated in oxidative stress, potentially leading to the neurologic damage characteristic of AD. In addition, poor-quality diets may also increase the prevalence of AD by eliciting cerebral inflammation, which may cause the neurologic damage that results in AD.^4,5,12

Many dietary risk factors for AD are shared with those implicated in atherosclerosis. Likewise, adherence to a Mediterranean-type diet is associated with decreased cognitive decline just as it is with a reduced risk for cardiovascular disease. Recent prospective studies have provided clear evidence that following a Mediterranean-type diet is associated with slower cognitive decline, reduced risk of progression from mild cognitive impairment (MCI) to AD, reduced risk of AD, and a decreased all-cause mortality in AD patients. These findings suggested not only a lower risk for AD, but also of predementia syndromes and their progression to overt dementia.^16,17

The key dietary factors from epidemiologic data that reduce AD risk are higher fish consumption (and omega-3 fatty acids), monounsaturated fatty acids (primarily from olive oil), light to moderate alcohol use (primarily red wine), and increased nonstarchy vegetable and fruit consumption. It is likely that it is the combination of all of these factors rather than any single one that provides the highest degree of protection.^16,17

One study in particular produced some very interesting findings. Given the ability of the Mediterranean diet to reduce inflammation and improve insulin sensitivity, it is assumed that this action may be of extreme importance in its ability to reduce AD. However, in a 4-year prospective study, the lower risk of AD with the Mediterranean diet did not seem to be mediated by C-reactive protein, fasting insulin, or adiponectin levels.¹⁸ Other aspects of the diet or specific foods are likely responsible, including dietary components that work directly on reducing β-amyloid formation or deposition. For example, polyphenols found in grapes, grape seed extract, and red wine have been shown to prevent β-amyloid formation and promote tau disassembly.^19,20 Pharmacokinetic studies in animals with radiolabeled grape polyphenols show absorption into the brain after oral administration.²¹

Even something as simple as celery (Apium graveolens) consumption may offer significant protection against AD. Celery and celery seed extracts contain a unique compound, 3-n-butylphthalide (3nB), that is both responsible for the characteristic odor of celery and its health benefits. In an animal model of AD, 3nB treatment significantly improved learning deficits as well as long-term spatial memory. 3nB treatment also significantly reduced total cerebral β-amyloid plaque deposition and lowered brain β-amyloid levels. It was also shown that 3nB markedly directed amyloid precursor protein processing toward a pathway that precludes β-amyloid formation. The researchers concluded, “3nB shows promising preclinical potential as a multitarget drug for the prevention and/or treatment of AD.”²²

The research on grape polyphenols and 3nB stimulates a powerful question. How many other foods contain unique compounds that address the pathophysiology of AD? From preliminary investigations it looks like a great many, especially promising are sources of phenols and polyphenols.^23–27

Estrogen

Estrogen has been promoted to offer protective and possibly therapeutic benefits in AD. However, the epidemiologic and clinical evidence to support the potential benefits of estrogen is contradictory. Sixteen population-based studies have indicated that women on hormone replacement therapy (HRT) had a lower rate of AD.²⁸ But the problem with these studies is that the women taking HRT were much healthier before taking the hormones compared with the control group (i.e., women who are prescribed HRT are less likely to have hypertension, diabetes, and history of stroke than nonusers).²⁸ Data from the only large randomized controlled trial published to date, the Women’s Health Initiative Memory Study, did not confirm these observations and even suggest an increase in dementia risk for women using HRT compared with controls, especially in the cases of women given HRT after menopause.²⁹ Clinical trials in women with AD have concluded that estrogen therapy does not improve dementia symptoms in women with AD and should definitely be avoided postmenopause.^30–32 Given the cloud of uncertainty about the benefits of HRT, it seems most reasonable to consider that at this point the risks of conventional estrogen therapy to prevent AD outweigh the benefits. See Chapter 188, on menopause, for a discussion of the critical differences.

Aluminum

Encouraging the avoidance of all known sources of aluminum—aluminum-containing antacids, aluminum-containing antiperspirants, cooking in aluminum pots and pans, the wrapping of food in aluminum foil, and the use of nondairy creamers—certainly seems appropriate. Aluminum is also found in baking powder and table salt, because it is added to keep them from becoming lumpy. In addition, citric acid, as well as calcium citrate supplements, appear to increase the efficiency of absorption of aluminum (but not lead) from water and food.³³ Aluminum absorption can be decreased by magnesium, because magnesium competes with aluminum for absorption, not only in the intestines but also at the blood–brain barrier.³⁴ A diet rich in magnesium is recommended. Have the patient focus on unprocessed foods; avoid milk and dairy products; and increase the consumption of vegetables, whole grains, nuts, and seeds—all good sources of magnesium.