Light in the Shadows

Brian Stauffer /

Albert Hofman is exploring an apparent decline in new cases of Alzheimer’s disease.

“She sits on a bed with a helpless expression. What is your name? Auguste. Last name? Auguste. What is your husband’s name? Auguste, I think.… What is this? I show her a pencil. A pen…. When objects are shown to her, she does not remember after a short time which have been shown. In between, she always speaks about twins.… When she has to write ‘Mrs. Auguste D.,’ she writes ‘Mrs.’ and we must repeat the other words because she forgets them. The patient is not able to progress in writing and repeats, ‘I have lost myself.’”

This conversation is more than 100 years old, drawn from the case notes of German neurologist Alois Alzheimer on the first patient diagnosed with the disease that would come to bear his name. But her suffering is all too familiar today. She is the grandmother who can no longer recognize her grandchildren or her own reflection in the mirror, the beloved spouse drifting away, the strong parent reduced to childlike dependency. With this disease’s power to eat away at the brain, dislodging memories and unwinding personality, it’s no wonder that a 2011 survey from the Harvard T.H. Chan School of Public Health found that Alzheimer’s is second only to cancer of the diseases we most fear.

Call it the dark side of our increasing life span. Age is the strongest predictor of who will suffer Alzheimer’s. Risk doubles every five years after age 65, and those who have reached 85 have about a 50 percent chance of developing the disease. As people live longer around the world, the number living with Alzheimer’s is expected to skyrocket. In the U.S. alone, the Alzheimer’s population may triple to 15 million by 2050. Or it may not—if scientists discover, in the absence of a cure, how to prevent or delay the disease.

Thirty years ago, Albert Hofman, the Stephen B. Kay Family Professor of Public Health and Clinical Epidemiology and chair of the Department of Epidemiology, was one of the few scientists raising the alarm about this potential demographic time bomb. But now, surprisingly, he sees a sliver of hope for a brighter future. New research by Hofman and other epidemiologists suggests that in the United States and Europe, at least, rates of new cases of Alzheimer’s are actually on the decline. If these trends continue, Hofman suggests, more people than predicted may be able to stave off the disease until later in life, or avoid it altogether.

The key piece of the puzzle, Hofman says, is getting a firm grip on the factors that may keep Alzheimer’s at bay. “When the end of the story of Alzheimer’s is written, it will be because of prevention.”


Alzheimer’s disease can take root in the brain decades before symptoms appear. The spark that sets it off remains in question, but the havoc it wreaks on the brain is indisputable: Amyloid beta-protein forms sticky plaques outside neurons, damaging their ability to communicate with other cells. Tangles of the tau protein form within cells, severing their transport system and starving them to death. While current treatments ease symptoms, there is no cure.

Hofman believes that better heart health may be behind the apparent decline in Alzheimer’s. By practicing healthy habits that we should be following anyway— keeping high blood pressure and high cholesterol in check, exercising, and not smoking—we may be preserving our brains and minds as well.

Beyond a patient’s age, disease risk is difficult to predict and diagnose. Although Hofman and other researchers have worked to develop tests that rely on blood markers, cerebrospinal fluid, and brain imaging, these methods are currently too inaccurate and expensive to use beyond a research setting. And they have not proven to be more reliable than a patient’s age at predicting risk.

In 1991, researchers found a genetic culprit in APOE4, a variant of a gene involved in making a protein that helps carry fat in the bloodstream. This variant, it turns out, may also help produce amyloid plaques. To date, it’s the strongest genetic risk factor for late-onset Alzheimer’s (the most common form of the disease, with symptoms developing after age 60). But carrying the APOE4 gene doesn’t mean that developing the disease is a given. The genetic prognosis for rare early-onset familial Alzheimer’s is much more dire. This form of the disease is linked to a few genetic mutations and can induce symptoms at a devastatingly young age—usually the 50s, but in rare cases even as young as the teens or 20s. People with one of these mutations almost certainly develop the disease and have a 50 percent chance of passing it on to their children.

The search for an Alzheimer’s cure has focused on stopping the spread of amyloid beta plaques, but several recent high-profile clinical trials of drugs targeting it have failed. To Hofman, this suggests that the plaques may be a consequence of the disease rather than its cause. Far before the plaques develop, other biological changes may be at work. For example, arteries narrowed from atherosclerosis may limit oxygen to the brain, and brain inflammation may also be involved in the complex cascade leading to Alzheimer’s disease pathology and symptoms.

Hofman wants to better understand these elusive mechanisms and the early-warning signs of the disease’s relentless assault on the body. It’s the kind of challenge that has sparked his enthusiasm for epidemiology since medical school. The idea that answers to the mysteries behind the causes, progress, and treatment of disease are calculable is what makes him tick, he says.

Tall and gray-haired, with long fingers that are in motion as he speaks and seem to shape his ideas from the air, Hofman sets off the clipped rhythms of his native Dutch with a physical lyricism. “Epidemiology is an integrating force in medicine and public health,” he says. “It’s at the root of everything we do.” When a colleague passed him an article about Alzheimer’s disease in the early 1980s, he quickly began to delve into its demographic trends and baffling causes. “I saw that epidemiologists had to get to work on this problem. That’s what this field is for.”

Common Questions, Clear Answers about Alzheimer’s Disease

Albert Hofman, Stephen B. Kay Family Professor of Public Health and Clinical
Epidemiology and Chair, Department of Epidemiology (Photo: Kent Dayton / Harvard Chan)

Q: Are environmental chemicals linked to Alzheimer’s?

A: Probably not. There is no convincing evidence for that hypothesis, although exposure to aluminum has been proposed. While agricultural pesticides have also been suggested as possible culprits, there is little evidence to back up that idea.

Q: What can a young adult do to prevent the disease?

A: One of the strongest current recommendations—and one that will likely hold up and be strengthened—is to eat a healthy diet and exercise regularly. A healthy heart usually means a healthy brain.

Q: Should I get genetic testing for Alzheimer’s?

A: There are many genes involved in Alzheimer’s—we currently know more than 30—but their effects are very small. Knowing about your genetic makeup does not currently have any implications for behavior or treatment.


Hofman has had a long association with the Harvard Chan School. He has taught an annual summer course in clinical epidemiology since becoming an adjunct professor in 1998, dividing his time with his home institution, Erasmus Medical Center in Rotterdam, Netherlands, where he served as a professor and chair of the epidemiology department. He joined the School’s faculty permanently in January 2016 as a visiting professor, before becoming the department chair and assuming his professorship in July 2016.

He brought with him access to the Rotterdam Study, a long-running cohort investigation he started in the Netherlands of people over 45. At the School, he has launched a consortium that links the study to seven other cohorts focused on Alzheimer’s in the United States and Europe. Combined, they bring together approximately 80,000 people, including about 15,000 with Alzheimer’s—amassing a precious trove of data that researchers can mine for insights into Alzheimer’s mysteries. In the coming years, they hope to add recently formed cohorts from Brazil, China, India, and Japan.

“A professor of mine in medical school would ask a lecture hall full of students how many had a family member with cardiovascular disease, and most hands would go up,” Hofman says. “I ask my classes now about Alzheimer’s disease, and it’s the same thing. Everyone has been touched.”

Albert Hofman, Chair, Department of Epidemiology

Already, Hofman and colleagues have seen signs of a wave of healthier brains. In two cohorts, the number of study participants who developed new cases of dementia dropped between 1990 and 2010, and brain scans of younger participants are showing fewer early markers of Alzheimer’s than older participants had at the same age.

These findings back a study by other researchers published last November in the Journal of the American Medical Association that found the proportion of older U.S. adults with dementia, including Alzheimer’s disease, declined from 11.6 percent in 2000 to 8.8 percent in 2012. In real-life terms, this  meant an estimated million fewer people developing dementia over that 12-year period, according to the researchers.

Hofman believes that better heart health may be behind the decline. That’s good news, he says, because vascular diseases are preventable. By practicing healthy habits that we should be following anyway— keeping high blood pressure and high cholesterol in check, exercising, and not smoking—we may be preserving our brains and minds as well.

He also sees signs in his cohorts that improved access to education from the mid- to late 20th century may be a factor. But it’s not clear whether this is due to changes in the brain itself or to the healthier lifestyles usually associated with more education. Both intellectual and social stimulation have shown promise in other studies—perhaps because they protect the brain’s cognitive reserve by enriching neural tissue and pathways.

A report released by the National Academy of Sciences this past June offered three recommendations for dementia prevention: cognitive training, controlling blood pressure, and physical activity, although the authors conceded that the evidence to support the recommendations was only modest. The first randomized controlled trial to test multiple avenues for preventing dementia—including diet and exercise, controlling vascular and metabolic health, and cognitive and social stimulation—showed some success when it was pioneered in Finland, and it is now being scaled up to other sites in Europe, Australia, Singapore, and the U.S.

But scientists across the field say more research is needed. In the U.S., funding Alzheimer’s disease research has been a rare example of bipartisan unity. Last spring’s congressional budget agreement included a $400 million increase to Alzheimer’s research funding at the National Institutes of Health (NIH), bringing the annual budget for this work to nearly $1.4 billion. More cooperation will be needed in the coming years, with the NIH estimating that at least $2 billion a year will be necessary to meet the first goal of the National Plan to Address Alzheimer’s Disease: to effectively treat and prevent the disease by 2025.


Hofman’s research agenda for the years ahead includes tantalizing questions that he hopes the expanded pool of study participants will help him answer. What’s behind the apparent link between metabolic syndrome and Alzheimer’s? Are subtle changes in the way a person walks an early warning sign for Alzheimer’s, as they are for Parkinson’s disease? What explains the apparent trend that people are dying sooner after diagnosis—later onset of the condition or some other factor? As Hofman analyzes data from more cohorts, he’s eager to see if the trends suggesting a decline in Alzheimer’s are showing up in other parts of the world.

Hofman’s new scholarly home is also likely to open up new research possibilities. He says he is thrilled to have the chance to discuss ideas with colleagues in “the most important department of epidemiology in the world.” The department has hosted giants in the field like the late Brian MacMahon, chair for over 30 years and best known for his work on risk factors for breast cancer and lung cancer, and the late Dimitrios Trichopoulos, Vincent L. Gregory Professor of Cancer Prevention and professor of epidemiology, who was renowned for his work on the Mediterranean diet and the health effects of passive smoking. New faculty have also made their mark, like those working on causal inference—a set of methods that Hofman foresees as being helpful in teasing out the complex chain of connections between Alzheimer’s and factors like diet and physical exercise.

As Hofman sees it, the biggest challenges in Alzheimer’s will be to find preventable causes and to detect groups of people who are particularly at risk for the disease.


Although Hofman has family members who have suffered from Alzheimer’s, he’d rather talk about the universality of the disease.

“A professor of mine in medical school would ask a lecture hall full of students how many had a family member with cardiovascular disease, and most hands would go up,” he says. “I ask my classes now about Alzheimer’s disease, and it’s the same thing. Everyone has been touched.”

Hofman recently participated in an “Ask Me Anything” online Q&A session on the website Reddit, inviting members of the public to talk to him about Alzheimer’s. The internet is a minefield of bad information about Alzheimer’s, from exposés on the supposed harmful effects of living near a power line to the latest miracle cure made from turmeric. Hofman fielded a range of questions—many of which seem tinged with a sense of fear or fatalism.

For Hofman, the aim was not only to deliver his public health message but also to let people know that researchers are working hard to help stop this devastating disease. “It’s important to defeat the fatalistic idea that Alzheimer’s is something that simply comes with aging and you can’t do anything about it,” he says. “We are studying it, and we will find the causes.”

Amy Roeder is associate editor of Harvard Public Health.