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Evan Vucci

There had been early clues, but it was a family game of dominoes around Christmas 2021 that convinced Susan Stewart that something was wrong with her husband. Then 75 and retired, Charlie Stewart struggled to match the dots on different domino tiles.

Susan assumed it was a vision problem. Charlie’s memory was fine, and he had no family history of dementia. But months later the Marin County, Calif., couple were shocked to learn that his domino confusion was a sign he had a lesser-known variant of Alzheimer’s disease. For patients with this variant, called <a href="https://www.alz.org/alzheimers-dementia/what-is-dementia/types-of-dementia/posterior-cortical-atrophy" target=_blank>posterior cortical atrophy</a>, the disease begins with problems affecting vision rather than memory.

The unusual early symptoms mean that thousands of people may go years before receiving the correct diagnosis, experts said.

That may change with the first large-scale international study of the condition, <a href="https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(23)00414-3/fulltext" target=_blank>published Monday in the journal Lancet Neurology</a>. An international team led by researchers at the University of California at San Francisco studied records of 1,092 PCA patients from 16 countries and found that, on average, the syndrome begins affecting patients at age 59 ― about five to six years earlier than most patients with the more common form of Alzheimer’s.

Although the number of patients with PCA has not been established, researchers say that the variant may account for as many as 10 percent of all Alzheimer’s cases; that would put the number of Americans with the condition close to 700,000.

“We have a lot of work to do to raise awareness about the syndrome,” said Gil D. Rabinovici, one of the study’s authors and director of the UCSF Alzheimer’s Disease Research Center. “One thing that we found in our large study is that by the time people are diagnosed, they’ve had [the disease] for quite a few years.”

The study authors said they hope greater awareness of the syndrome will help doctors diagnose it earlier and will encourage researchers to include patients with PCA in future Alzheimer’s clinical trials.

PCA was first described in the medical literature in just five patients in 1988, and for a long time the condition was not well understood. Doctors in different parts of the world did not use the same criteria to make the diagnosis. Experts didn’t agree on a <a href="https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1016/j.jalz.2017.01.014" target=_blank>formal description of the condition</a> until 2017, when it was published in the journal Alzheimer’s &amp; Dementia.

What little public attention PCA has received up to now was mainly due to British author and humanist <a href="https://www.washingtonpost.com/entertainment/books/terry-pratchett-author-of-discworld-fantasy-series-dies-at-66/2015/03/12/657009f4-c8d2-11e4-b2a1-bed1aaea2816_story.html" target=_blank>Terry Pratchett</a>, who announced in December 2007 that he had been diagnosed with the syndrome. He pledged to donate $1 million to the Alzheimer’s Research Trust in the United Kingdom and collaborated with the BBC in 2009 on the two-part documentary “Terry Pratchett: Living With Alzheimer’s.”

The new PCA study, which began in 2021, found that on average PCA is not diagnosed until about four years after the onset of symptoms. The syndrome’s progression can vary, however. Some patients begin to experience symptoms of memory decline within a year or two of their first vision symptoms.

The study also found that PCA patients had levels of harmful amyloid and tau plaques in their brains that match those seen with the more common version of Alzheimer’s. The plaques are found in a different part of the brain in PCA: regions at the back of the brain that are involved in vision, such as the occipital and parietal lobes.

Experts say the most common early symptoms involve difficulties reading and driving. Motorists with PCA can have a hard time judging distances. Patients also struggle when reading at night. Some people have difficulty understanding a complex scene; for example, finding their way through a grocery store to pick up one specific item.

For unknown reasons, a disproportionate number of people with PCA — about 60 percent — are women.

Because the first symptoms are visual, patients often start by seeing their primary doctor and getting referred to an optometrist, then an ophthalmologist and, finally, a neurologist.

As with Alzheimer’s, there is no cure for PCA. Occupational therapy and other services for visual impairment can help patients with the syndrome. Patients can also benefit from simple lifestyle changes: reading large-print books, using better lighting at home, and highlighting the boundaries of uneven surfaces such as stairs.

Some patients can also be helped by <a href="https://www.washingtonpost.com/health/2023/07/03/alzheimers-drug-leqembi-fda-approval/" target=_blank>treatments to improve Alzheimer’s symptoms</a>, such as the class of drug known as cholinesterase inhibitors. They may also benefit from taking disease-slowing treatments such as anti-amyloid antibodies.

The early visual symptoms often result in PCA patients being excluded from clinical trials, said Marianne Chapleau, a postdoctoral fellow at UCSF and one of the study’s lead authors.

“We thought it was really important to shed light on this syndrome,” she said, so that “clinicians and researchers who conduct clinical trials can have a better sense of who these people are.”

He defied Alzheimer’s for two decades. Scientists want to know how.

Carolyn Fredericks, an assistant professor of neurology at Yale School of Medicine who was not involved in the study, called the paper “important” and “an area of Alzheimer’s research that has been so understudied.”

“It’s a syndrome not too many general practitioners or even general neurologists see on a regular basis,” Fredericks added.<b> </b>Her research specialties include less common Alzheimer’s variants. She estimated that in a decade of practice she has seen at least 100 PCA patients.

Robert Sergott, director of the neuro-ophthalmology service at Wills Eye Hospital in Philadelphia, called the new study, which he did not work on, “excellent work and very necessary” for explaining the diagnosis of PCA, its biological markers and the demographics of its patients.

“Once we have these well defined, then we can start to develop rational clinical trials” of possible treatments, he said.

In retrospect, the Stewarts realized that Charlie’s first symptoms occurred more than a year before the domino game. In the summer of 2020, Susan, a former neurology nurse practitioner, noticed that Charlie was filling in the wrong spaces in his checkbook. She took over checkbook-keeping duties, a switch Charlie was only too happy to make.

He had also made a few errors in calculating tips at restaurants and found it hard to organize the tools in the garage. There had been one or two times when Susan worried about her husband’s driving. When he was merging left, he seemed to have difficulty seeing the traffic coming up behind him, “which was terrifying,” Susan said.

Late in 2021, during a regular eye exam, Charlie’s optometrist noticed what appeared to be a problem with vision on his left side, and referred him to a retinal specialist. The specialist found everything normal. An ophthalmologist even reported that Charlie had excellent 20/20 vision.

It was a neuropsychologist in February 2022 who first suggested Charlie’s condition might be PCA. The word Alzheimer’s, however, was not used. His diagnosis was confirmed at a meeting that May with a neuro-behaviorist.

In September, a doctor showed Charlie a PET scan of his brain, and the problem was evident. “In living color you could see the damaged components,” Charlie said, “and it was unmistakable and undeniable.”

In the three years since the domino game, his symptoms have worsened. From time to time he has more pronounced memory problems, especially involving short-term memory.

During a recent interview, he stopped talking abruptly, paused and admitted, “I just can’t finish the sentence.”

Once an avid home improver, Charlie now has difficulty doing touch-up painting work and has had to let Susan take over.

“A very unfortunate part of this is that it gets frustrating,” Susan said, “which leads to him raising his voice sometimes. This is a very mild-mannered person.”

Still, Charlie remains very active in mind and body. He loves to garden, walks three to six miles per day in the San Pablo Bay National Wildlife Refuge, “reads constantly,” and enjoys doing Wordle and the New York Times crossword puzzle.

He takes the Alzheimer’s medication Aricept, which helps patients with attention and memory. In December, he joined a clinical study, which involves receiving injections of a gene-modifying drug believed to reduce the levels of harmful tau protein. He receives one injection every 12 weeks but does not know whether he is receiving the drug or a placebo.

He also writes about his experiences with PCA for his local newspaper.

“I try to keep them uplifting,” Charlie said, “because it’s easy to find articles about how awful the disease is. So we’ll leave those to other people to write.”

2011, Pulitzer Prize, explanatory reporting

2014, Pulitzer Prize finalist, feature writing

2006, Pulitzer Prize finalist, explanatory reporting

2003 Pulitzer Prize finalist, explanatory reporting

Though The Earth Gives Way

One In A Billion: The Story of Nic Volker and the Dawn of Genomic Medicine 

University of Toronto BA English Literature

Mark Johnson joined The Washington Post in July 2022 after 22 years at The Milwaukee Journal Sentinel, where he covered health and science. He wrote about the first person to survive rabies without vaccine, and reported on the first use of full gene sequencing to diagnose and treat a new disease. 

Mark Johnson

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