amyloid plaques, neurofibrillary tangles and degeneration of multiple neurotransmitter systems. a. A tissue section from region CA1 of the hippocampus of an Alzheimer’s patient exhibits many neurofibrillary tangle-bearing pyramidal neurons and neuritic plaques, examples of which are demarcated. In addition, diffuse amyloid deposits (yellow) are present. b. Hippocampal pyramidal neurons receive synaptic inputs from several different types of neurotransmitters including excitatory glutamatergic and inhibitory GABAergic inputs from intrinsic hippocampal neurons, and modulatory inputs from cholinergic neurons in the basal forebrain, serotonergic neurons in the raphe nucleus and noradrenergic neurons in the locus ceruleus..

Interactions of Aβ oligomers and Fe²⁺ or Cu⁺ generates H₂O₂. When Aβ aggregation occurs at the cell membrane, membrane-associated oxidative stress (MAOS) results in lipid peroxidation and the consequent generation of 4-hydroxynonenal (4HNE) a neurotoxic aldehyde that covalently modifies proteins on cysteine, lysine and histidine residues. Some of the proteins oxidatively modified by this Aβ-induced oxidative stress include membrane transporters (left), receptors (R), GTP-binding proteins (g) and ion channels. Oxidative modifications of tau by 4HNE and other reactive oxygen species (ROS) can promote its aggregation and may thereby induce the formation of neurofibrillary tangles. Aβ can also cause mitochondrial oxidative stress and dysregulation of Ca²⁺ homeostasis resulting in impairment of the electron transport chain (ETC), increased production of superoxide anion radical. and decreased production of ATP. Superoxide is converted to H₂O₂ by the activity of superoxide dismutases (SOD) and superoxide can also interact with nitric oxide (NO) to produce peroxynitrite (ONOO*). Interaction of H₂O₂ with Fe²⁺ or Cu⁺ generates hydroxyl radical (OH*) a highly reactive oxyradical and potent inducer of MAOS which contributes to the dysfunction of the endoplasmic reticulum (ER).

Approaches that are being tested in clinical and/or primary prevention trials include Aβ immunization, Cu⁺/Fe²⁺ chelation, cholesterol-lowering drugs (statins), anti-inflammatory agents, antioxidants and folic acid. Epidemiological and animal studies suggest the potential benefits of cognitive stimulation, regular physical exercise and dietary restriction, but these remain to be critically examined in controlled prospective studies or clinical trials.