The first case of Alzheimer’s was described by Alois Alzheimer in 1906. The clinical description of dementia and decline of cognitive ability correlated with the presence of beta-amyloid plaques on the brain have been described as a principal feature of this disease. Plaques formed by deposition of the beta-amyloid peptide have been observed in Alzheimer’s patients’ brains in post-mortem analyses.  The formation of plaques has also been replicated in animal models. Studies with animal models also show that the extent of development of plaques corresponded with severe dementia and loss of cognition and memory, giving rise to the notion that beta-amyloid plaques are the causative agents of Alzheimer’s disease. Recent advances in imaging techniques, reported by Rabinovici and colleagues, which involve labeling with Pittsburgh compound B followed by positron emission tomography (PET) imaging, have been used to track the progression of Alzheimer’s in living patients. These authors suggest that although formation of beta-amyloid fibrils is seen in some patients at the initiation of the study, resultant dementia and progression of Alzheimer’s is not positively correlated with increased deposition of beta-amyloid fibrils.

Beta-amyloid peptide is produced when another protein, amyloid precursor protein (APP), is sequentially cut by enzymes beta- and gamma-secretase. Yet, recent clinical trials with molecules that can target the synthesis of amyloid plaques have not been successful. Drugs like Semagacestat and scyllo-inositol (both molecules can inhibit gama-secretase) have not been useful in reducing the loss of cognitive functions in patients. The beta-amyloid peptide forms soluble polymers in the cytoplasm before being deposited in the form of fibrils outside neurons. Tramiprosate was an experimental drug tried in clinical trials to inhibit the formation of these polymers. However, this molecule did not improve cognitive deficits in a Phase II trial with patients. New molecules that may help to stop the formation of fibrils include a couple of antibodies and another compound known as PBT2 (reviewed in Teich et. al.).

If inhibitors of plaque formation are not delivering a landslide victory against Alzheimer’s then it is likely that these structural abnormalities (amyloid plaques) are actually markers for an advanced stage of the disease and not the definitive and sole causative agents. Also, amyloid plaques have been noted in geriatric patients who did not suffer from Alzheimer’s disease.

Research into familial Alzheimer’s disease (FAD) where Alzheimer’s disease can be traced through genetic lineage says that other factors, in addition to metabolism of APP, are likely to be involved in the progression of this disease. FAD-linked genes produce proteins that help to operate and maintain lysosomes in brain cells. Lysosomes are small chambers within cells specialized in degrading proteins as well as organic materials ingested by cells. These intracellular compartments facilitate recycling of organic components within a cell. Analyses of FAD-linked genes suggest that when this mechanism of degradation is hindered, it may set off events that lead to the formation of amyloid plaques and ultimately Alzheimer’s disease. In addition to impaired protein processing events in neurons, genes involved in FAD are also involved in regulating the transmission of chemical signals received at the cell membrane, into the cytoplasm.

Struble and colleagues have proposed that reduction in brain metabolic activity precedes both the onset of dementia as well as deposition of beta-amyloid fibrils. Therefore, decline in brain metabolism is more likely to be the trigger for initiation of Alzheimer’s disease.

Evidence from research suggests that deposition of beta-amyloid plaques is likely to be a late stage event in the progression of Alzheimer’s disease and other cellular events regulated by gene products of FAD-linked genes may be involved in early stages of Alzheimer’s before cognitive impairment is evident.

Why, then, are plaques formed at all? One possibility is that toxic intracellular events that lead to processing of APP into beta-amyloid peptide as well as other lysosomal activities eventually result in death of neurons and the deposition of plaques is a commemorative event. The precursors of plaques can remain soluble in the cytoplasm in the early stages of development of the disease and they change into an insoluble form (plaque deposits) only after neurons die. They are probably traces of neurons which are killed by incipient Alzheimer’s disease. This hypothesis, if tested and found true, would also explain why drugs that stop the polymerization of beta-amyloid peptide have shown somewhat better results than those which inhibit production of the peptide itself. For now, scientific evidence suggests that the fundamental cause of Alzheimer’s may lie elsewhere and amyloid plaques are not necessarily the singular causative agents of Alzheimer’s disease.

References

Pimplikar SW, Nixon RA, Robakis NK, Shen J, & Tsai LH (2010). Amyloid-independent mechanisms in Alzheimer’s disease pathogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience, 30 (45), 14946-54 PMID: 21068297

Rabinovici GD, & Jagust WJ (2009). Amyloid imaging in aging and dementia: testing the amyloid hypothesis in vivo. Behavioural neurology, 21 (1), 117-28 PMID: 19847050

Struble RG, Ala T, Patrylo PR, Brewer GJ, & Yan XX (2010). Is brain amyloid production a cause or a result of dementia of the Alzheimer’s type? Journal of Alzheimer’s disease : JAD, 22 (2), 393-9 PMID: 20847431

Teich AF, & Arancio O (2012). Is the amyloid hypothesis of Alzheimer’s disease therapeutically relevant? The Biochemical journal, 446 (2), 165-77 PMID: 22891628

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