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Alzheimer’s disease was a complete mystery in the late 1980s. In autopsies, pathologists could see the ravages left in patients’ brains, but how and why did the process start? There were rare families in which the disease seemed to be inherited, though, and perhaps there was a gene mutation that might provide a clue to what goes awry. The problem was finding those families.

In the late 1980s, a woman who lived in Nottingham, England, contacted John Hardy at University College London and asked if he and his team wanted to study her family. Her father was one of 10 siblings, five of whom had developed Alzheimer’s disease, and she could trace the disease back for three generations. Their investigation led to the discovery of a gene mutation that, if inherited, always caused the disease. The gene was presenilin, and its protein was the amyloid precursor protein, or APP. Every person in that family who inherited the gene overproduced amyloid and got the disease. For the first time, scientists had a clue to what starts the horrendous destruction of brain cells in Alzheimer’s disease. And for the first time, by putting that gene mutation in mice, they could study Alzheimer’s in a lab animal, look for drugs to block the gene’s effects and finally use the tools of science to look for a cure.

GINA KOLATA

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Helen Hobbs, a professor at the University of Texas Southwestern Medical Center and a Howard Hughes Medical Institute investigator, and her colleague Jonathan Cohen were intrigued when they read a short paper describing a French family with stunningly high levels of LDL cholesterol, the dangerous kind, and early deaths from heart attacks and strokes. The family members turned out to have a mutation in a gene, PCSK9, whose function was unknown. Dr. Hobbs and Dr. Cohen began to wonder: If too much PCSK9 caused heart disease, would people who made too little be protected? They scrutinized genetic data from a federal study and found that about 2.5 percent of blacks had a mutation that destroyed one copy of the gene; 3.2 percent of whites had a mutation that hobbled a copy of the gene but did not destroy it. In both cases, less PCSK9 was made and LDL levels were low. The people with the mutations seemed almost immune to heart disease, even if they had other risk factors like high blood pressure, smoking or diabetes.

What would happen if someone had both copies of PCSK9 destroyed? Dr. Hobbs found one young woman, an aerobics instructor, without PCSK9. She was healthy and fertile even though her LDL level was 14, lower than seemed possible (the average is 100). That discovery led to a race among drug companies to make cholesterol-lowering drugs that mimicked the effects of the PCSK9 mutations. The result is drugs that can make LDL levels plunge to the 30s, the 20s, even the teens. The first two such PCSK9 inhibitors were approved this year for people with high cholesterol levels who cannot get them down with statins and are at high risk of heart disease.

GINA KOLATA