The fact that the gene coding for APP is located on chromosome 21, one of the regions linked to one type of familial Alzheimer disease and to the duplicated chromosome in Down syndrome, in which Alzheimer changes almost inevitably occur with aging (see further on), suggests that the overproduction of amyloid and all its Aβ residues are causative factors in the disease. Furthermore, the ratio of Aβ42 to Aβ40 is increased in Down syndrome. Another suggestive connection has been the finding that there are genetic defects in the genes encoding APP and in a pair of endosomal proteins termed presenilin 1 and 2 in some familial forms of Alzheimer disease. The presenilins are catalytic components of γ secretase, the enzyme that produces the Aβ42 fragment. Mutations of presenilin 1 and 2 also increase the relative levels of Aβ42. It should be noted that mutations of the APP and presenilin genes explain only a very small proportion of Alzheimer cases (Terry). Transgenic mice that express human Alzheimer disease-associated mutations in APP or presenilin genes develop plaques with Aβ42 but not neurofibrillary tangles. Many of the relationships and mechanisms depicted in Fig. 38-2 are derived from the understanding of genetic forms of Alzheimer disease; the extent to which they will be implicated in the native disease is unknown. However, some form of disruption in these mechanisms is likely to be involved.
There is still uncertainty regarding a direct relationship of amyloid deposition to the loss of neurons and brain atrophy in Alzheimer disease. Alternatively, soluble oligomers of Aβ amyloid may be the toxic agents, whereas the emphasis until now has been on the effects of visible assemblies of insoluble amyloid fibrils. Similarly, TDP-43, the product of inadequate functioning of the progranulin gene, is also deposited in neurons and may play a substantial role in the severity of expression of Alzheimer disease; this protein has been implicated in the pathogenesis of frontotemporal dementia and motor neuron disease, both discussed later in the chapter. Others have questioned the amyloid hypothesis and pointed to the imprecise relationship between amyloid deposition and neuronal loss, even suggesting that aggregated amyloid is in some way a protective mechanism of cells. It seems most likely that amyloid alone is not solely responsible for Alzheimer disease, particularly in cases of late-life onset. Amyloid may accelerate degeneration of neurons and once dementia is established, there may be little additional accumulation of amyloid.
The importance of neurofibrillary tangles has also been a matter of intense investigation, and the manner in which amyloid deposition relates to tangle formation is unclear. Unexplained also is prominent senile plaque formation in some cases and neurofibrillary tangles in others. One prevalent view is that the tangles are a secondary phenomenon. However, PET studies, such as the one by Wang and colleagues, indicate that tau deposition in the inferior temporal and parietal cortices, more clearly than amyloid, differentiate normal older individuals from those with mild cognitive impairment or Alzheimer disease and that tau is more closely aligned with temporal lobe cortical atrophy. This accords with neuropathology studies that show diffuse amyloid deposition throughout the cortex and more focal tau deposition that corresponds to cognitive ability in these states.
In their review, Hardy and Selkoe, authoritative investigators in this field, pointed out that “Although the amyloid hypothesis offers a broad framework to explain AD pathogenesis, it is currently lacking in detail, and certain observations do not fit easily with the simplest version of the hypothesis.”