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Alzheimer's Disease

The molecular origins of the disease are coming to light, suggesting several novel therapies

Vernon Ingram

Figure 1. Six self-portraitsClick to Enlarge Image

The essential nature of Alzheimer's disease—losing your mind—terrifies everyone who has seen a friend or family member fall to its advance. Alzheimer's disease is devastating, and, despite great strides in recent years, still puzzling in its cause and mechanisms.

Some cases, fortunately few, clearly run in families and strike early; the rest begin later, but show an equally relentless decay of personality. For the minority carrying early-onset Alzheimer's mutations, the genetics are cruel and implacable: If you have inherited one of those genes, you will develop the disease. Yet the great majority of cases do not demonstrate such a clear inheritance pattern. Of this majority, some represent inherited genes that give a higher-than-average chance of developing the disease. Other cases arise in the absence of known genetic risk factors and show no hereditary pattern. What turns these genetic chances into reality? More important, what can we do to stave off the disease once a diagnosis is made?

The answer to the first question is disappointing. Science doesn't know yet. What is known is that age is the most important risk factor. Even the familial form of the disease does not usually begin until the mid-50s, and the nonfamilial (more common) form starts much later, in the 70s or 80s. However, in both cases the brain pathology and cognitive deficits are the same, pointing to a common molecular mechanism.

The answer to the second question—how to treat the disease—is close but also out of reach. There are very few approved treatments for the psychological symptoms (memory loss, disorientation, personality changes), and the few that have been described seem to afford only very partial and short-term relief. Therapeutic options do exist for relieving secondary symptoms, including depression, anxiety, restlessness, hallucinations and sleep disorders. However, a cure or treatment for the underlying cause of Alzheimer's remains elusive.

Figure 2. Alzheimer's diseaseClick to Enlarge Image

Mercifully, the gloom of this dark preface is lifting. Many research groups around the world are seeking to understand the disease at a fundamental level. Already, many insights into Alzheimer's disease pathogenesis have emerged, several promising drug therapies are on the horizon, and a few candidates are entering clinical trials. These compounds pursue diverse strategies, but all aim to halt or even reverse the molecular events that are precursors to cell dysfunction and cell death. In our laboratory, my colleagues and I have developed a model that explains the neurodegenerative mechanism of Alzheimer's disease, and we have some promising data on a novel method of blocking this pathogenic process.

We believe the root cause of Alzheimer's pathology is a toxic interaction of a protein fragment called amyloid-β 1-42 with specific ion channels in the outer membrane of neurons. Our data show that this interaction causes an abnormal influx of calcium ions (Ca2+) into the cell, disrupting cellular machinery and inhibiting the neuron's ability to respond to incoming stimuli. Over time, the Ca2+ dysregulation effectively poisons the cell. We have been able to arrest this process by introducing small "decoy peptides" that bind Aβ1-42 and force it from its destructive shape into a benign complex with the decoy. In this article I shall summarize the current understanding of Alzheimer's disease, a few of the best therapeutic candidates, and our own work.

Figure 3. Plaques and tanglesClick to Enlarge Image

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