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.
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.
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.
Familial Alzheimer’s is transferred to offspring such that each child has a 50 percent chance of inheritance if one parent has it. How many of us are walking around with these loaded guns? The information is seductive. Many of us want to peek at our genomes. Is there information in there that could tell us we are smarter, or in more danger, than we think? Yet, a firestorm erupted in recent weeks as the FDA temporarily suspended 23andMe’s genetic testing services over concerns about the reliability of their tests. One reason for the concern was that there was a single approval process for hundreds of disease markers tested. But another was that families may carry a multitude of rare mutations, but taken out of the genetic context of that family, a single mutation may not predict a disease, Sherman Elias, a clinical geneticist and professor emeritus at Northwestern University, told me.
A decade ago, “genome-wide association studies” emerged as a tool to examine large datasets, sometimes up to 50,000 people, in order to identify gene variants that cause common diseases. The studies were based on the premise that any common disease must have common genetic drivers. In some cases, it turned out to be true. Recent large-scale studies on late-onset Alzheimer’s have pointed to 22 “areas of interest,” including mutations in a gene called BIN1 on chromosome 2 and CLU on chromosome 8, each which have a role in sweeping out old proteins from the attics of our brains. And yet, a decade after the first draft of the human genome was released, at a cost of $3 billion dollars, the public is clamoring for more of its secrets, and a means to treat disease. Where are all of the drugs?
Alzheimer’s is so common, shouldn’t we have a drug? In fact, many common diseases are turning out to have diverse and collective genetic origins, or etiologies. Consider that the human genome contains 23,000 protein coding genes. Many experts had expected it would carry 100,000 genes. The initial reaction to this finding was that the genome was surprisingly simple. How wrong we were. We now know that the genome contains heaps of code that is transcribed into RNA but never becomes protein, the so-called non-coding RNA. (The group ENCODE recently reported 75 percent of the genome is published into RNA while only about 2 percent codes a protein). Some of it, called lincRNA, is very long. Call it the Dark Matter of the Genome, if you like, because for the most part, we don’t know how it works.
In my day job, I investigate the role of RNA in Alzheimer’s disease. I work on computer problems. One of these problems is how RNA is processed in Alzheimer’s brains. RNA is tailored by seamstresses in our cells, leading to many species or “isoforms” of RNA and protein. I like to think of these isoforms as tiny dresses. A single gene can be patterned to build many styles of a dress. And some RNA can regulate other RNA, tuning its expression “up” or “down,” deciding how many dresses are made. Furthermore, a series of “epigenetic” molecules attaches to the structure of the genome and switch genes “on” or “off.” Thus, our genes are regulated by disparate forces, which decide when, which, and how many of these dresses are sewn in the cellular factory.
Alzheimer’s research is undergoing a shift to a “systems” or “networks” approach, where instead of just pinpointing a single mutation or genetic variant, we are now looking at networks—groups of molecules that go to work together on shifts on the cellular factory floor. We can see major shifts in RNA occurring in brain tissue, but the causes of these changes are often invisible to us. So far, a large component of it appears to us as Dark Matter.
Alzheimer’s disease has, for decades, been dominated by the “amyloid cascade hypothesis,” the theory that large plaques of amyloid-beta (building up outside cells) and tau proteins (building up inside cells) starve and kill neurons.
Yet one emerging theory suggests that it’s the smaller forms of amyloid-beta molecules that cause all of the trouble. William L. Klein, a neurobiologist at the Cognitive Neurology and Alzheimer’s Disease Center at Northwestern University, is among the scientists credited with originating this “small species camp,” more technically known as the “Abeta oligomer cascade hypothesis.” His claim: A smaller form of amyloid beta, or “oligomer,” acts as a neurotoxin, adhering to cell receptors and jamming communication. Klein’s team found that they bind to a spot near a receptor in the hippocampus called NMDA, which has long been implicated in the creation of new long-term memories.
The NMDA receptor works like a tiny gate that opens and closes and lets ion signals jump from cell to cell. The toxins were binding to a spot near the receptor and keeping the gates jammed open (a “gain-of-function” disorder) disrupting proper cell-to-cell communication, and along with it the creation of new synapses, the ability to make new memories, and what neuroscientists call “plasticity.” In fact, the Federal Drug Administration approved an NMDA receptor inhibitor called Memantine in 2003 as a treatment for moderate to severe Alzheimer’s disease, but scientists were without good explanation for why it had modest benefits.
Klein’s team introduced more evidence for this theory when he showed that this small species toxin was binding to a complex that reduced the function of an insulin receptor. Insulin uptake is needed for the creation of long-term memories. Indeed, Alzheimer’s is now thought of, by some, as a form of diabetes, or Diabetes Type 3. (Suzanne Craft at the Wake Forest School of Medicine is now leading a trial on the effects of insulin nose spray on Alzheimer’s.)
An intriguing new trend in modern medicine is technology that calls the body’s own defense systems to the task of fighting diseases. In cancer research, the “immunotherapeutic approach” is back in vogue. Alzheimer’s research has a similar vanguard of drug candidates.
The idea with these candidates is to stimulate the body’s own waste disposal systems to swab the sticky plaques out of the brain on their own. Some Alzheimer’s researchers say they can now jumpstart the waste disposal systems, sort of like giving the body’s own tiny garbage men a pay hike to do their job better.
At least two research groups have demonstrated the power of this strategy. A few years ago, J. Paul Taylor, a former assistant professor of neurology at University of Pennsylvania, published findings that modulating the expression of a certain gene, which alters epigenetic code, could reduce or accelerate plaque buildup in the eyes of fruit flies. Ben Bahr, a chemist at University of North Carolina-Pembroke, and Dennis Wright, a chemist at University of Connecticut-Storrs, are the cofounders of Synaptic Dynamics. They discovered a compound that could increase the function of one of the tiny garbage men in the cell, a lysosome, which lassos old proteins and dissolves them with enzymes. In fact, the group showed it could clear amyloid beta species proteins by 63 to 73 percent in Alzheimer’s disease model mice, and it improved cognitive functioning.
There is no mainstay drug yet, but science is on the march. Researchers like me continue to investigate the mysterious non-coding RNA. Ben Bahr’s group said it would stimulate the brain’s lysosome to clean up plaques in the brain. Suzanne Craft is setting out to prove that she could treat the disease with an insulin nose spray. William Klein is developing the first antibody to target the “small species” of the protein residues.
I traveled to visit my father in Chicago. He told me that he had finished writing a play. It was about a man who had a scar high on his cheekbone, which he got when he crashed through a storefront window the day he learned he was going to have a son. The man had not always been the best father. He was tired and despondent, but he never developed dementia. Though old, he never lost his senses. When his son went to visit him, the man locked the door. But his son broke down the door, and he told his father how important he had been. And that he needed him.