Alzheimer’s Disease: The Great Morbidity of the 21st Century
Neuroangiogenesis (NAG) provides a vascular basis for understanding Alzheimer’s disease, senile dementias and cognitive decline with aging
Studies on the Etiopathology of AD
Alzheimer’s disease has been diagnosed on two levels—histologically by the presence of amyloid plaques (AP) and neurofibrillary tangles (NFT) in the brain and/or, in their absence, clinically by key cognitive symptoms and signs—loss of memory, orientation and reasoning. The pathogenesis of AD is likely multifactorial, entailing several or many sequential cellular and biological interactions. The ultimate defect is impaired synaptic connections due to neurons altered in physiology or reduced in number or size. Many investigators of AD have focused their attention instead on the penultimate cause—that is, on various physical or biochemical changes in the brain – for example, the presence of AP and NFT.
For several decades the amyloid cascade theory proposed by Hardy and Higgins in 1992 has dominated research into the etiopathology of AD. The production and assembly of these aberrant protein deposits have been extensively explored and postulated to act as foreign bodies in the brain, inducing there an inflammatory response with neuronal damage and death. AP first appears in the brain as an amyloid precursor protein (APP), which is cleaved by an APP secretase into the amyloid beta protein (Aβ). AP has been postulated to have a toxic effect on neurons directly or, when aggregated, via free radical formation, which leads to “oxidative stress” and the resulting degeneration and death of neurons. NFT consists of a hyperphosphorylated protein (tau), which destabilizes the neuronal cytoskeleton and aggregates into clumps/tangles. Numerous studies have concerned the clearance of AP across the blood brain barrier and Aβ/APP lowering drugs, whereas others have identified genetic alleles controlling AP. It’s not clear whether the presence of AP or NFT is a primary, penultimate event or secondary to some underlying process.
Two troubling reservations about the amyloid theory are that some persons without symptoms of AD have many cortical Aβ deposits and that, as John Hardy and Dennis Selkoe put it, “the number of amyloid deposits in the brain does not correlate well with the degree of cognitive impairment” experienced by patients. This suggests that some other primary factor or condition is responsible for AD but may promote AP and NFT formation secondarily.
Other investigations have centered on the deficiency of acetylcholine in AD brains or on the excess of glutamic acid in nerve cells with a resulting calcium influx. Elemental aluminum, iron and mercury in the brain have been postulated as catalysts for free radical generation and the oxidative stress mentioned above. Protein oxidation, lipid peroxidation and other biochemical aberrations have been found in AD brains, as well as changes in the capillary basement membrane and glia. Scores of genes have been identified that influence early onset versus late onset forms of the disease. The literature is immense. But none of these areas of study of AD has provided a general unifying theory of its etiopathology.
An overview of AD might focus on three levels—genetic differences (which ultimately determine most aspects of brain biology/pathology), the proximate cause (toxic agents, vascular defects and so on) and peripheral influences (for example, risk factors). This essay concerns mainly one particular proximate cause—a diminished level of neuroangiogenic factors, as explained next.