ALZHEIMER'S DISEASE (AD)

Alois Alzheimer (German neurologist 1864 -1915) described between 1907 and 1911 two structural changes in the brain of two patients who had suffered from memory deficits: 1) amyloid plaques, and 2) neurofibrillary tangles. His chief, all-time great psychiatrist Kraepelin, nearly immediately called it "Alzheimersche Erkrankung" ("Alzheimery" disease). The original microscopic slides and notes of Alzheimer at the University of Munich were very recently retrieved and modern re-analyses confirmed that Alzheimer, using different technical vocabulary, had most correctly recognized and described the typical changes of the disease carrying his name (Eur Arch Psychiatry Clin Neurosci 1999; vol. 249, supplement III, pages III-10 to III-13).

Plaques form predominantly outside of neurons of the cerebral cortex, with a predilection for certain brain regions that are important for local cortical networking (pyramidal cells of cortex layers III and V providing cortico-cortical connections known as distal association areas). The destructive process spares the cortex responsible for motor activity (no paralysis) and sensing (no deficits in feeling). An important plaque component is the protein known as beta amyloid (β-amyloid, abbreviated Aβ). The biochemical and genetic characteristics of this protein were first described between 1984 and 1987. Beta amyloid is derived from a larger protein (beta amyloid precursor protein, abbreviated APP).

According to one prevailing concept Alzheimer's disease is caused by an accumulation of breakdown products of beta amyloid precursor protein. The accumulating breakdown products are thought to exert direct "toxic" effects on brain nerve cells. The concept is known as the amyloid cascade hypothesis. One important observation is that genetic diseases associated with either an overproduction or altered (enhanced) degradation of beta amyloid precursor protein (APP) result in early onset forms of Alzheimer's. The gene responsible for the production of APP is located on the small chromosome No. 21. Individuals born with an extra copy of this chromosome (trisomy 21, known as Down syndrome and previously called "Mongolism") overproduce APP. This overproduction leads to an accumulation of APP degradation products, abundant amyloid plaque formation, and early onset dementia. Contrarily, two mechanisms of abnormal APP processing may invite amyloid accumulation. First, there are about 10 inheritable APP variants (mutations) exhibiting increased tendency to fragment into toxic amyloid products (Ab42). Second, the enzymes that break down APP occur in inheritable variants (mutations) accelerating the formation of toxic amyloid. Enzymes identified as important for the breakdown and disposal of APP are known as secretases alpha, beta, and gamma. Normally, APP is predominantly cleaved by alpha secretase, a pathway that prevents formation of toxic amyloid (Ab42). Beta and gamma secretases in combination degrade normally only a small fraction (10%) of APP to its toxic fragments. Gamma secretase is a complex of at least 4 proteins (presenilin-1, nicastrin, APH-1, PEN-2). Presenilin-1 appears to be the component conferring enzyme (gamma secretase) activity, whereas the other components act as modulators that either inhibit (APH-1) or enhance (PEN-2) enzyme activity of presenilin-1 (Nature 2003; 422:438-441). Presenilin-1 occurs in at least 60 known mutations associated with increased breakdown of normal APP to its toxic products. The mutations cited here are important for the understanding of the processes underlying Alzheimer's disease. However, it is important to recognize that only a small fraction of persons (about 5-7 %) suffering from Alzheimer's disease can be currently demonstrated to have abnormal genes (mutations) inviting increased amyloid generation and plaques formation.

Whereas amyloid is predominantly deposited outside of nerve cells to produce amyloid plaques, neurofibrillary tangles occur inside of the nerve cells. All cells contain a multifunctional system of protein threads (filaments) known as cytoskeleton. The cytoskeleton is made up of three types of filaments, actin filaments, intermediate filaments, and microtubules. Neurofibrillary tangles are deposits of a protein called tau (τ) that occurs normally in association with the microtubule filaments. Tau protein forming tangles occurs as paired twisted (helical) filaments to which many phosphate groups have been attached (so-called hyperphosphorylation). The relationship between amyloid plaques and neurofibrillary tangles, structures composed of unrelated proteins, has been the subject of speculations for many years.

Current evidence supports the view that tangles occur as a consequence (epiphenomenon) of beta amyloid accumulation: 1) in genetically-engineered (transgenic) mice expressing (overproducing) either human amyloid precursor protein or human tau or both, mice with combined amyloid/tau expression produce much more abundant tangles compared with mice expressing tau only, i.e., presence of amyloid appears to aggravate tangle formation. 2) Injection of beta amyloid into mouse brain tissue evokes the formation of tau-positive tangles. Also, transplantation into the brain of healthy recipient mice of mouse brain tissue genetically modified to produce amyloid promotes Alzheimer-like disease in the neighboring normal recipient brain tissue (Nature Neuroscience Feb 2003). This strongly suggests that extracellular diffusion of amyloid can damage normal neurons not generating by themselves increased amounts of amyloid. 3) in a familial disease arising from a mutation producing a variant tau, there is striking neurofibrillary tangle formation associated with a neurodegenerative syndrome (dementia plus Parkinsonism), but there is no amyloid plaque formation. Thus, amyloid plaques can cause tau tangles (points 1 and 2), but vice versa tangles do not obligate amyloid plaque formation (point 3). Note, however, that tangle formation by itself can produce nerve cell deterioration and death leading to dementia, suggesting that amyloid deposition may partly act indirectly by stimulating the formation of tau tangles. In fact, it has been suggested that tangle formation is the structural abnormality correlating best with dementia severity.