The Pathophysiology of Alzheimer’s Disease

The characteristic features associated with AD include brain atrophy, amyloid plaques, and neurofibrillary tangles, and these abnormalities generally affect the medial temporal lobes the earliest and most intensely. Currently, there is compelling evidence that all types of AD, irrespective of age of onset, result from the neurotoxic effects of increased brain levels of soluble oligomeric forms of A-ß peptides, derived from the amyloid precursor protein (APP), and from its aggregated forms (amyloid) as present in senile plaques and in the walls of small cerebral vessels.

In cases of early-onset familial AD caused by genetic mutations, the increase in A-ß is secondary to the increased production of the peptides A-ß-40 and, especially, A-ß-42 through the increased activity of ß and γ secretases, two cleavage enzymes for APP. In contrast, in sporadic late-onset AD, it has been generally thought that decreased clearance of A-ß is the proximate cause. In support of this hypothesis, brain regions associated with increased amyloid deposits in sporadic AD show lower levels of VPS26 and VPS35, two retromer proteins involved in the intracellular compartmental trafficking of the A-ß peptides.

Interestingly, there is recent evidence that the APOE є4 allele may also increase A-ß peptide production, raising the possibility that increased A-ß production contributes to the development of sporadic AD in elderly individuals with this allele. There is evidence that increased A-ß peptide levels facilitate the abnormal phosphorylation of the τ protein, which in turn leads to its forming intracellular neurofibrillary tangles.

This supports the general belief that the neurofibrillary tangles are a secondary phenomenon; however, memory deficits correlate more with the presence of neurofibrillary tangles than with plaques. The earliest pathological alterations of AD are usually seen in the entorhinal cortex and nearby CA1 subfield of the hippocampus, both structures in the medial temporal lobe critical for the formation of new memories, thereby explaining the prominent memory symptoms that are typically present as an initial symptom of AD.

AD is eventually accompanied by the pronounced degeneration of cholinergic neurons in the nucleus basalis with associated reduced levels of acetylcholine, and this loss seems to contribute significantly to memory dysfunction. The degeneration of dopaminergic neurons in the noradrenergic nucleus locus ceruleus, the serotonergic dorsal raphe nucleus, and the dopaminergic substantia nigra and the significant reductions in somatostatin-like immunoreactivity and corticotropin releasing hormone (CRH) immuno- reactivity in the neocortical brain regions have also been demonstrated in AD and might contribute to the noncognitive symptoms associated with this disease.

Paradoxically, there is evidence, albeit indirect, that AD may be accompanied by overactivity of neuronal synapses using the neurotransmitter glutamate, possibly secondary to the loss of the high-affinity glutamate transporters that has been reported in AD. The overactivation of glutamate N-methyl-D-aspartate (NMDA) receptors produces excitotoxic effects, especially in areas such as the hippocampus and entorhinal cortex, in which the density of these receptors is high.

These brain regions have been implicated in learning and memory and show profound abnormalities, including atrophy even in the earliest stages of AD, supporting a possible role for disturbances in glutamatergic neurotransmission in the cognitive and degenerative alterations associated with this disorder. There is also some empirical support for oxidative stress and inflammation having etiological roles in the pathogenesis of AD.