ALZHEIMER'S DISEASE (AD)

To what extent functional deterioration of existing brain nerve cells represent true (genetically determined) aging of nerve cells or contrarily the influence of highly prevalent diseases (nutrition-related disease, high blood pressure, high blood cholesterol and neutral fats [triglycerides], "embolic brain disease") is quite unclear. Previously, adverse effects of high blood cholesterol ("bad cholesterol" or LDL cholesterol exceeding 100mg/dl) on the blood vessels were erroneously restricted to a disease of large and medium-sized arteries (arteries developing in their walls highly characteristic "fatty lesions" known as atheromas). However, in the 1970ies we and others demonstrated in animals and humans that high cholesterol impaired small blood vessels in the absence of atheromas. Important features of this "non-atheromatous" disease of small blood vessels includes an impairment in the dynamic regulation of vessel diameter (impaired vasodilation) and a marked impairment in the ability to grow new small blood vessels in response to increased blood flow requirements (impaired adaptive angiogenesis). These impairments may critically restrict organ blood flow including that to the brain. Additionally, advanced fatty lesions (atheromas) of large and medium-sized arteries upstream of the brain (ascending aorta, transverse aorta, neck arteries [carotids], and large brain arteries) can fragment and release small atheroma fragments that are carried by the bloodstream as so-called emboli. Small emboli get stuck at the level of small blood vessels and their entrapment affects the vessels' structural and functional integrity. This type of small blood vessel disease is known as (brain) athero-embolic disease. Another common type of embolic disease arises from blood clots forming on the inner surface of heart chambers with impaired mechanical activity. In particular, atrial fibrillation, a most common chronic arrhythmia in the elderly population, may invite the formation of blood clots (thrombosis) on the inner surface of the left-sided small heart chamber (left atrium), with clot fragments of varying size getting loose to reach the brain circulation (brain thromboembolic disease). Both athero- and thrombo-embolic disease may produce widespread small brain lesions ("microinfarcts") that exhibit characteristic distribution patterns on brain imaging (brain scan and MRI). This disease may affect brain function and simulate partly Alzheimer's dementia. Only large emboli acutely plugging large brain arteries tend to produce clinically obvious stroke events. However, even sizable damage from embolic events may remain unrecognized, a phenomenon known as silent brain infarction. Silent brain infarction as demonstrable by magnetic resonance imaging of the brain is a common and important risk factor of dementia in the elderly (New Engl J Med 2003;348:1215-1222). A special type of small brain blood vessel disease (cerebral amyloid angiopathy, CAA) very frequently complicates Alzheimer's disease (this is discussed below under "Amyloid Plaques"). Finally, high blood pressure and diabetes may both directly and indirectly cause and/or aggravate small brain vessel disease. In brief, very common forms of small brain vessel disease caused by partly interrelated mechanisms may affect the brain to produce mental deficits simulating Alzheimer's disease: 1) direct vessel damage from high blood cholesterol, 2) atheroembolism, 3) thromboembolism, 3) amyloid angiopathy, 4) high blood pressure, and 5) diabetes.