Alzheimer’s disease can develop years earlier in individuals with depression, anxiety or other psychiatric disorders than in those without, finds a new preliminary study released Wednesday, in advance of an American Academy of Neurology virtual gathering.

The study indicates that not only can Alzheimer’s disease develop in people with either depression or anxiety — factors previously linked to an increased risk of dementia — years before those with neither disorder, but also that it can develop in people with both even earlier. 

Reductions in the age at which symptoms became apparent doubled with each additional psychiatric disorder in the preliminary study, with some people experiencing symptoms up to nearly seven-and-a-half years earlier, being as young as 57 on average.

Zachary Miller, study author and associate professor of neurology at the Memory and Aging Center at the University of California, San Francisco, argues that psychiatric prodromes, or the time intervals from the onset of unusual behavioral symptoms to the onset of psychotic symptoms, could explain the age differences. 

"We can't really answer the chicken-or-egg question here," Miller said. "It could be that people who are younger when they get Alzheimer's disease have more of this behavioral psychiatric prodrome, and it also could be that having a history of these psychiatric disorders makes your brain vulnerable in some ways to Alzheimer's disease." 

Miller favors the former explanation, which is also what the study supports. The different profiles of people who are younger when they develop Alzheimer's disease suggest that the disease, while not necessarily more aggressive, has a "slightly different physiological mechanism in which depression and anxiety symptoms and the like are more profound,” said Miller.

The preliminary study will be presented during the AAN's 73rd annual meeting in April. 

The research, which was led by UCSF and supported by funding from the National Institutes of Health’s National Institute on Aging, comes as the rates of both depression and anxiety in U.S. adults spiked amid the COVID-19 pandemic.

Depression prevalence has tripled since the start of the pandemic, while the rate of older U.S. adults reporting anxiety or depression reached 24% in August, up from 11% in 2018. The rate of both major depressive disorder and generalized anxiety disorder is estimated to be around 60%.

An initial study from the same UCSF center specialized in atypical and early-onset forms of dementia looked at typically known risk factors, including hypertension and diabetes, among others.

For the follow-up, researchers were inspired to hone in on psychiatric conditions by the first case of Alzheimer’s disease, in which the clinical psychiatrist and neuroanatomist Alois Alzheimer had an early-onset form of the disease as well as psychiatric symptoms. With the initial study’s collection of 750 early-onset and 750 late-onset cases, some factors led researchers to believe that psychiatric conditions could progress further in younger and older forms of the disease. 

For the new research, a total of 1,500 individuals with Alzheimer’s disease who went into the UCSF Memory and Aging Center were screened for a history of psychiatric disorders. Researchers leveraged diagnostic labels, which are used to group patients for treatments and research.

But they encountered a problem: The labels proved too restrictive. An individual with bipolar disorder, for example, could have additional symptoms of depression that are distinct, even if that person wasn't diagnosed with depression, Miller noted — and the effect of those symptoms was as strong as a formal diagnosis. In this way, the researchers felt the diagnostic labels alone weren't telling the full story of what patients might be experiencing. So while bipolar disorder would already be considered its own entity under such labeling, the researchers decided to make signs of depression a separate entity, as well.

"At some point, we said, 'What if we drop the labels and just look at the burden of diagnosis?'" Miller said, referring to a person’s number of diagnostic labels. "And that's when we saw that there were these declining differences at age at onset."

It was also when the main findings became apparent: Individuals who were only reporting depression were 2.1 years younger at onset, whereas those who only had anxiety were three years younger. But the two combined had an even greater effect on the age at onset.

The decision to focus on the burden of diagnosis was the turning point in the research, which then broke patients down into groups with one label compared with none, two compared with one or none and three or more labels compared with fewer. Although the researchers still referenced diagnostic labels, they made adjustments for situations where patients exhibited symptoms of psychiatric disorders but were not formally diagnosed.

Of the patients, 47% did not have any psychiatric label, 29% had just one, 22% had two and 1% had three or more. Groups that had two conditions were almost overwhelmingly individuals who had depression and anxiety, while those who had three of these labels experienced depression, anxiety and post-traumatic stress disorder.

Individuals with only one psychiatric disorder developed Alzheimer’s disease one-and-a-half years earlier than those with no psychiatric disorders. Those with two disorders developed symptoms 3.3 years earlier. And those with three or more disorders developed symptoms 7.3 years earlier compared with those who did not have any labels. The average age in the group of 705 individuals without any psychiatric label was 65 years old, Miller added, providing a reference point for the age at which other patients might experience early onset of symptoms.

Shifting the focus away from any particular label and toward the overall burden of diagnosis to observe the differences also led the researchers to suggest that each psychiatric diagnosis could be contributing its own pathophysiological burden, and that this understanding could lead to new opportunities for novel therapeutic interventions.

Miller lamented the challenges posed by diagnostic labels, which can also carry a stigma for patients. He points to a movement for research on psychiatric symptoms to limit use of diagnostic labels and focus instead on whether a person has depressive symptoms, anxiety symptoms or others to understand the overall profile of different behaviors.

Despite having inherent imprecision, the diagnostic labels “are still telling us something,” said Miller. They do point to potential underlying mechanisms at play in the disease and disorders, he said, though which ones exactly remains unclear.

The study serves as a jumping-off point for additional research by measuring the profile of each individual who had an earlier onset. 

“Many new avenues opened up in this research,” Miller added, including how the research relates to neuroimaging and the neuropathological factors; the inflammation and hyperexcitability that are known to underlie Alzheimer's disease, anxiety and depression; and how factors influencing earlier or later onset can be better defined. Miller hopes the study will raise issues of brain health and maintaining brain health among the public.

The preliminary study, “History of Psychiatric Disease Inversely Correlates with Age of Onset in Alzheimer’s Disease,” was released Feb. 24. The authors of the study were Emily Eijansantos, University of California, San Francisco School of Medicine; Isabel Allen, Jessica Deleon, Rian Bogley, David Perry, Virginia Sturm, Howard Rosen, Lea Grinberg, William Seeley, Bruce Miller, Gil Rabinovici, Maria Gorno Tempini and Zachary Miller, UCSF Memory and Aging Center; Stephanie Grasso, University of Texas; and Nicole Rogers, Global Brain Health Institute. ​​​​