Depression and anxiety are linked to earlier onset of Alzheimer’s disease (AD), new research shows.

Investigators found the age of onset of AD is about 2 years earlier among patients with depression and 3 years earlier among those with anxiety vs those without these disorders. In addition, having more than one psychiatric diagnosis pushes the age of AD onset even earlier.

The findings underline the importance of screening for cognitive decline in older patients, including those with psychiatric conditions, study author Zachary A. Miller, MD, associate professor of neurology, University of California San Francisco Memory and Aging Center, told Medscape Medical News.

“I think that as part of healthy aging, we should be doing some level of screening for cognition, just like everyone should get a colonoscopy at age 50,” said Miller.

Patients should be monitored if they have symptoms of depression or anxiety, or if these are not well treated and “if they have cognitive complaints in addition to those psychiatric and mood concerns, we definitely want to know who they are,” he added.

The findings will be presented at the American Academy of Neurology (AAN) 2021 Annual Meeting in April.

Dose-Dependent Effect?

Depression has been established as a risk factor in AD that may accelerate the development and disease course, the researchers note. However, they add, less studied are the effects of other mood disorders, psychotic disorders, and posttraumatic stress disorder (PTSD) on AD.

To investigate, researchers screened 1500 patients with AD from the UCSF Memory and Aging Center for a history of various psychiatric conditions. Results showed 43.3% of subjects had a history of depression, 32.3% anxiety, 1.2% bipolar disorder, 1% PTSD, and 0.4% schizophrenia.

Compared with those without depression or anxiety, participants with these conditions were significantly younger at age of AD onset  (2.1 and 3.0 years, respectively; P < .001).

Miller noted that patients “ran the gamut” of depression symptoms, but that those with and without a formal diagnosis of depression “were performing very similarly” regarding AD age of onset.

The researchers looked at when patients had their first symptoms of depression before AD onset (within 2 years, 2-10 years, or more than 10 years). Again, “it didn’t matter when the psychiatric symptoms presented,” in terms of earlier AD onset, said Miller.

The difference in age at AD onset doubled with each additional psychiatric diagnosis. The presence of only one psychiatric disorder was associated with a 1.5-year younger age, two psychiatric conditions with a 3.3-year younger age, and three or more diagnoses with a 7.3-year younger age (P < .001).

“We’re finding that the symptomatic profile of individuals who develop AD at a younger age has more of these psychiatric features, and the more features and intensity of those features, the younger the age of onset,” said Miller.

He noted the group with two psychiatric conditions “almost exclusively included just those with anxiety and depressive symptoms”, and that those with three or more conditions were mostly those with PTSD who also had depression and anxiety.

More Questions than Answers?

There are different ways to interpret the data, said Miller, who is a behavioral neurologist.

“We think that when AD begins, it attacks or starts very early on in lower regions of the brain, the mid-brain and brain stem areas, and that some of the earliest pathological symptomatic features of AD may actually be things like a depressive prodrome. But it could be that having a history of depression taxes those same areas that makes patients more vulnerable to getting AD,” he said.

The researchers looked deeper to better understand what’s driving earlier AD onset in patients with psychiatric disorders. They examined demographics and typical AD risk factors such as hypertension, hyperlipidemia, diabetes mellitus, education and APOE4.

They found that cohorts with depression and anxiety included more women. This might suggest women who get AD “are more prone to show depression and anxiety as an earlier feature,” said Miller.

These participants also had fewer typical AD risk factors. Miller noted that because they were younger, they were less likely to have cardiovascular and cerebrovascular risk factors.

Investigators also examined what Miller called “novel” factors associated with AD, including autoimmune diseases such as type 1 diabetes, multiple sclerosis, seizure history, and others.

“The folks with depression happened to have a slight statistically significantly greater amount of autoimmune disease, so more had a past medical history of autoimmune disease,” said Miller. The P value for the association between depression and autoimmune disease was 0.01.

Neuroinflammation may play a role in the association between depression and earlier AD onset. Miller noted a great deal of research has looked into inflammation as a possible underlying cause of depression.

Although the direction of the relationship is unclear, “my bias is that a certain amount of systemic inflammation may cross over into the brain and effect certain areas and thus you present as depressed,” said Miller.

The study also showed that participants with anxiety had a greater frequency of seizures (P = .002). Miller pointed to several previous studies that suggested a connection between seizures and anxiety, the underlying pathophysiologic mechanism possibly involving neuronal hyperexcitability.

The researchers did not look at the role of psychiatric medications. Miller said “it would be fantastic” to look “into the longitudinal arena” and determine how being treated and not being treated is related to disease progression.

He acknowledged the research doesn’t fully explain why patients with psychiatric conditions may be more vulnerable to earlier AD onset. “In the end, it probably raises more questions than it provides answers, but hopefully it generates interest and excitement.”

A “Welcome Addition”

Commenting on this study for Medscape Medical News, John C. Morris, MD, professor of neurology and director of the Alzheimer Disease Research Center at Washington University in St. Louis, Missouri, said it “provides welcome additional information about the possible relationships” between depression and dementia, particularly AD.

A strength of the study was that the authors didn’t focus only on depression, but considered other psychiatric conditions, said Morris, who was not involved with the research. However, he noted PTSD, bipolar disorder, and schizophrenia “were so infrequent as too be difficult to analyze.”

Morris pointed to some “caveats” to the study that may be addressed during the presentation at the AAN Meeting.

First, patients with depression who come to a memory and aging center typically have very mild depressive features, what’s termed “subsyndromal symptomatic depression” or SSD. Such patients, said Morris, would not qualify for a diagnosis of major affective disorder.

He said he’s keen to learn more about the severity of participants labeled with “depression” and “anxiety.”

In addition, it’s unclear if patients with depression and anxiety came to the UCSF center with their memory concerns 1-3 years earlier than those who didn’t report depression and anxiety. “Perhaps AD dementia began at roughly the same age in both groups, but the “depression” group sought a diagnosis at an earlier stage,” said Morris.

Another caveat is the analysis didn’t take into account the potential effects of medications used to treat depression and anxiety, which may have worsened memory and thinking.

“Perhaps it wasn’t the psychiatric disorders per se that were responsible for the observed younger age at onset but instead the meds used to treat the disorders,” said Morris.

He cited a study providing “very preliminary evidence” that the common antidepressant drug escitalopram, a selective serotonin reuptake inhibitor, may benefit those at risk for AD dementia by reducing the amount of amyloid-beta 42, a hallmark Alzheimer’s protein, in the cerebrospinal fluid and presumably in the brain.

Morris agreed that the nature of the possible association between depression and dementia, particularly AD dementia, “still remains debatable.”

The study was supported by the National Institute on Aging . Miller and Morris have disclosed no relevant financial relationships.

American Academy of Neurology (AAN) 2021 Annual Meeting: Presentation 003. To be presented April 20, 2021.

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