The Alzheimer’s Alarm Clock

Alzheimer’s disease is a progressive neurological disorder characterized by memory loss and confusion, and is the most prevalent age-dependent dementia (1). The major risk factor of Alzheimer’s disease is age. Less than two percent of all people inflicted with Alzheimer’s disease are below the age of forty-five. This increases to approximately ten percent over the age of sixty-five, and jumps dramatically to forty-seven percent in the over eighty-five population (2). The familial forms of Alzheimer’s disease account for less than ten percent of all affected individuals, and the majority of these cases become affected after the age of sixty (3). This signifies a biological alarm clock that appears to awaken this dormant disease after the age of fifty in most individuals, and the mechanism responsible still remains unclear.

One of the most prevalent neuropathological features of Alzheimer’s disease is the deposition of amyloid in the brain, in addition to selective neuronal loss and neurofibrillary tangles. Amyloid accretions exist as either amorphous, diffuse deposits or as a dense senile plaques, which stain positive with Congo red (4). The principle constituent of the amyloid deposits is a peptide denoted amyloid β (Aβ), which varies from 39 to 43 amino acids in length, the most abundant forms being 40 and 42 amino acids (Aβ40 and Aβ42, respectively) (5). The Aβ protein is normally cleaved from the proteolytic processing of the amyloid precursor protein (APP) by two enzymes, β secretase and α secretase (Figure 1).

Figure 1: β-Secretase and α-secretase compete for the amyloid precursor protein (APP) to produce either of their respectful large extracellular fragments termed APPs. The C-terminal fragments remaining in the membrane are cleaved by γ-secretase in the transmembrane region, to release either Aβ or P3 peptides and the intracellular release of the APP intracellular domain (AICD).

β-secretase, also known as β-site APP cleaving enzyme (BACE), leads to the production of Aβ peptide after β-secretase cleavage, whereas β-secretase cleavage produces the non-toxic P3 peptide (4). Both Aβ40 and Aβ42 can form amyloid fibrils, but are also associated with other structural forms in the progression to the fibril state. The monomeric form of the Aβ peptide has generally been considered to not be a neurotoxic species.

It has been shown that the density of senile plaques does not increase with age, rather, patients switch from a plaque-free state to plaque-bearing (3). The amyloid plaques develop from initially being non-neurotoxic into mature, senile neuritic plaques. The number of these senile neuritic plaques increases after the process is first initiated, with the number approximating to the degree of cognitive impairment (3).

Thus the question still remains as to what major physiological change(s) occur which allow for the initiation of Alzheimer’s disease. One possibility is that a regulatory change occurs, leading to the usage of different signaling pathways, hormones and transcriptional regions. This process can be clearly defined in women as menopause, which typically occurs between the ages of forty-five and fifty. A similar change may also occur in men around the same time period. This may be the natural winding down of the human clock that inadvertently awakens the processes leading to Alzheimer’s disease. Greater understanding of the changes that occur later in life is required for prevention of age-dependent diseases such as Alzheimer’s. Prevention will not be possible until the factors that initiate the clouds of plaques in the brain are clarified; this leaves only symptomatic treatment for Alzheimer’s sufferers. However, recent findings have shed light on possible methods for treatment.

Recently, BACE knockout mice were shown to lack Aβ and appear phenotypically normal (6). As well, BACE null mice which overexpress human APP have their memory and cognitive impairment rescued. Thus inhibitors targeted directly to BACE would decrease the amount of newly formed Aβ peptides and decrease the level in storage pools. This inhibitor would need to be combined with another drug that could be used to remove the Aβ peptide reserve. It has been shown that a large amount of Aβ peptide is bound and transported by albumin in human plasma (7). This pool would need to be removed for the successful treatment of senile plaques by eliminating the presence of the Aβ peptide. A specific binding partner for the Aβ peptides is required in order to clear it from the body.

In summary, a prevention of Alzheimer’s disease will not be possible without a greater understanding of the physiological changes that are associated with aging. However, research is generating potential therapeutic strategies that can be used to eliminate the effects of Alzheimer’s disease. This includes a reduction in the produced Aβ peptide using a BACE inhibitor and a drug targeted directly at binding the Aβ peptides to remove them from the physiological pool. With such a potential therapy, the future of Alzheimer’s disease will be determined.


1. D.H. Small, et al., Nature Neuroscience 2:595 (2001).

2. R.N. Martins, J. Hallmayer, Pharmacogenomics J. 4:138 (2004).

3. D.G. Munoz, H. Feldman, CMAJ 162:65 (2000).

4. D.J. Selkoe, Annu. Rev. Neurosci. 17: 489 (1994).

5. G.G. Glenner, C.W. Wong, Biochem. Biophys. Res. Commun. 120:885 (1984).

6. M. Ohno, et al., Neuron 41:27 (2004).

7. A.L. Biere, et al., J. Biol. Chem. 271:32916 (1996).

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