Why Can't We Prevent Alzheimer's?

We got the human genome a decade ago. Where are the drugs?
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My grandfather was found wandering shoeless in the town where he was born, 50 miles from home. That was the first day we knew. Or, it was the last day we could pretend. A stranger placed a call to my father at his apartment in Evanston, Illinois, after finding my grandfather on those wintery streets, untucked and empty-eyed.

On a regular day, he’d take the “L” from Evanston into Chicago and place some bets at the track. He liked to play the ponies, and he whittled down his paychecks at the bar. My grandfather kicked alcoholism at age 65. He didn’t touch a drop for 16 years until his death, something he was proud of; but in the last decade, he was vanishing. On this day, alcohol couldn’t explain his disappearance. By the afternoon, something was amiss. Hours later, into the night, the telephone rang. Did we know an Anthony Kozubek?

He was a child raised in the depth of the Great Depression. He could fix anything. Repair your front steps. Fix your plumbing. Install new gutters. One time he visited our house, and within an hour was upon our roof. We didn’t have a ladder so he built us one. A few hours later, he built us a back staircase. He told us, maybe to build the lore of his hardscrabble life, that as a child he “recycled” his sister’s shoes for his by cutting off the heels.

The son of Polish immigrants, my grandfather grew up on a polyglot street, and he began drinking with purpose in his teens. My grandmother stowed money in cans so that he wouldn’t spend it. He was a boxer. Tall and lithe, he fought amateur Golden Gloves bouts in his Chicagoan youth in the 1930s. (His brother Joe traveled to New York and sparred with heavyweight champ Jack Sharkey). He fought and he drank, inside the ring and outside, and it continued while he served the U.S. Army’s Engineer Corp.

He didn’t talk about WWII, but years later we learned of his station transfers through the jackbooted continent based on records of his stints in the brig. The poor aren’t born into this world; they come crashing into it. When he learned he was having a son, my grandfather and his brother-in-law celebrated with drinking, stumbling and shattering a store-front display window, landing in a heap of plate glass.


Anthony Kozubek of the U.S. Army's 344th Engineer Regiment had his nose broken by the time of this picture due to a fistfight.

He would later suffer from late-onset Alzheimer's disease. (Jim Kozubek)

Years later, my father would scribble down notes in journals, detailing those past events, documenting hard lives that built the foundation for us. We had recovered my grandfather from those slippery streets, but his faulty memory couldn’t be rescued. In fact, his lack of recognition was jarring. When my father was preparing to remove his clothes from a dresser, he recalls, my grandfather protested, "You can't take those clothes, they belong to my son." Alzheimer’s "moments" drop like chasms.

And yet, this is not one elegiac story, it is many. Five million people in the United States have Alzheimer’s disease. This number will double in a decade. If any of us live to be 85, the chances of having the disease or some form of dementia is about one in three. The explanation for why some of us get it and some don’t is a largely unsolved genetic riddle. My grandfather eventually died from it. My grandmother is now 96-years-old, writes me cards with lacy cursive, and regularly beats me at Scrabble.

Recently, my father subscribed to a service that allowed us to mail in a cheek swab to learn about our genetic ancestry. I learned that I belonged to Haplogroup R—a type of ethnic branch on our genetic tree—that I am German and Polish (which I knew), and by a small fraction Ashkenazi Jewish (which I didn’t know), and I received a colorful map of my ancestors probable traipses through Europe. But though it was an option on the test, my father did not want to know about our risk for Alzheimer’s, it turns out. And for good reason—there is not a single meaningful drug to treat Alzheimer’s.

The role of genetics is far from clear for “late onset” Alzheimer’s. Consider that genes come in different versions, or alleles. The gene variant APOE4, which is a risk factor for the disease, differs from other versions by a single amino acid change. The mutation occurs in 14 percent of German people, for instance. How we live with APOE4 also matters. One in six boxers develops Alzheimer’s disease or Parkinson’s disease, known as “dementia pugilistica.” It can be useful to know if you carry APOE4. If you do, you shouldn’t overdo contact sports. Or start fistfights.

Dark Matter

All our lives, our genomes take on mutations. Often we are born with inherited chinks. Take amyloid precursor protein (APP), a gene processed by enzymes called alpha, beta, and gamma secretase. Mutations in APP, or PSEN1 and PSEN2 (the genes that build proteins that regulate secretases) can elevate some “isoform” species of APP. This imbalance, exacerbated by a declining brain’s reduced ability to clean it up, leads to a buildup of beta amyloid plaques, a defining trait of the disease. These mutations are drivers of “early onset” or “familial” forms of the disease, which can strike people as early as their 40s. Although geneticists call APOE4 a risk factor, since it adds to the chances we might get the “late onset” form of the disease, mutations in APP are strong causal predictors.

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Jim Kozubek is a science writer and computational biologist based in Cambridge, Massachusetts.

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