Midlife Anxiety Tied to Late-Life Dementia

Batya Swift Yasgur, MA, LSW

May 01, 2018

Moderate to severe midlife anxiety may be an independent risk factor for late-life dementia, new research shows.

Investigators reviewed the findings of four studies, encompassing almost 30,000 people. Individuals with midlife anxiety disorders or serious anxiety symptoms were significantly more likely to develop dementia in later life, on average at least a decade prior to their being diagnosed with dementia.

These findings excluded anxiety related to prodromal cognitive decline.

"These findings lay the foundation for considering whether older adults with a history of clinical anxiety should be screened for dementia, although, at this point, we think it is too early to suggest that clinicians screen middle-aged individuals with anxiety for early signs of dementia," lead investigator Natalie Marchant, PhD, lecturer and assistant professor, Division of Psychiatry, University College London, United Kingdom, told Medscape Medical News.

But "if anxiety is indeed a risk factor for dementia, this has implications for being better able to identify individuals at risk and to intervene early to reduce risk of developing dementia," she said.

The study was published online April 30 in BMJ Open.

Long Interval

"Depression has been consistently related to the development of dementia," the authors write.

Some research suggests that a long interval between the diagnosis of depression and the diagnosis of dementia suggests that depression is a risk factor rather than merely a prodromal symptom of dementia, they note.

The role of anxiety as a potential risk factor has been less studied than that of depression, although anxiety symptoms have been found to be commonly experienced in the years preceding a dementia diagnosis and have been associated with cognitive decline.

Most previous studies have investigated the association of anxiety and dementia during the 5 to 10 years prior to dementia diagnosis.

However, because the average length of prodromal preclinical cognitive decline is estimated to be 5 to 6 years, and mild cognitive impairment (MCI) may progress to Alzheimer's disease (AD) within 5 years, an analysis of studies in which there was an interval of at least a 10 years between anxiety assessment and diagnosis of dementia would provide a more accurate way of determining the likelihood that anxiety is independent from the dementia prodrome, the authors write.

"To date, there has been no systematic review to investigate the association between clinically significant anxiety and dementia," so the "aim of this study was therefore to review the literature examining the association...over a longer time scale (≥10 years)," they state.

"Depression has been identified as one risk factor for dementia, and since anxiety frequently co-occurs with depression and is a relatively prevalent disorder, we wanted to understand whether clinical anxiety was also associated with risk for dementia," Marchant explained.

"We included studies that had on average at least a 10-year time interval between assessment of anxiety and diagnosis of dementia to minimize the likelihood that anxiety was an early sign of dementia — what we call a 'prodromal marker' — because we were more interested to know whether it is an independent risk factor," she said.

The investigators searched three databases for all articles published through March 8, 2017, that investigated the association between anxiety and the incidence of either dementia or MCI.

To be included in their analysis, studies had to include an anxiety diagnosis or assessment of anxiety symptoms; to be population-based; to assess anxiety at least, on average, 10 years before final clinical assessment for dementia; and to focus on late-onset dementia diagnoses (age ≥65 years).

Of 3509 citations, the researchers identified four studies, involving 29,819 patients, that met their inclusion criteria.

Study sample sizes ranged from 441 to 27,136 patients. Participants were recruited from either the community, hospital inpatient/outpatient populations, or both.

All the studies assessed and controlled for a variety of demographic, medical, and psychiatric risk factors (eg, sex, age, family history, social class, and marital status).

Accelerated Neurodegeneration

All four studies found a "significant increase" in the number of dementia diagnoses in patients who either had a diagnosis of anxiety or who experienced clinically significant anxiety symptoms ≥10 years prior to their being diagnosed with dementia (Zilkens et al: odds ratio [OR] =1.61; 95% confidence interval [CI], 1.28 - 2.02]; Boot et al: OR = 7.4; 95% CI, 3.5 - 16; Gallacher et al: OR = 1.62; 95% CI, 0.59 - 4.41; Petkus et al: OR = 1.48; 95% CI, 1.01 - 2.18).

The association between anxiety diagnosis and later dementia was stronger in the retrospective studies that included lifelong diagnoses of anxiety in comparison with the studies that invesitgated the association over a shorter period.

In the study by Pelkus et al, the association remained, even when participants who developed dementia within 5 years of baseline assessment were excluded.

These findings "lend support that the associations found were independent of prodromal dementia symptoms," the authors comment.

Findings regarding the relationship between anxiety and other risk factors were inconsistent.

For example, the study by Boot et al found a stronger association between anxiety diagnosis alone and future dementia, vs either depression diagnosis alone or diagnosis of mixed anxiety and depression. The other studies did not assess the interaction between anxiety and depression.

All four studies were rated highly on the Newcastle-Ottawa Scale.

The researchers did not conduct a meta-analysis, owing to the heterogeneity of the studies.

Nevertheless, "despite the heterogeneity of the studies that were included in our review, all of the studies that met our inclusion criteria showed an association between clinically significant anxiety and diagnosis of dementia," Marchant noted.

"Additionally, we assessed the quality of these studies and found that they were all of good quality — meaning that they were fairly representative of the population and they accounted for a number of other factors that could have influenced their findings," she continued.

"From that basis, we concluded that there is a relationship between midlife moderate to severe anxiety and risk of dementia," she said.

The authors note that the longer interval between anxiety and dementia diagnosis "may provide evidence for a common biological pathway linking anxiety, depression, and dementia."

This hypothesis suggests that an abnormal stress response, which typically is associated with anxiety, may accelerate the aging of brain cells and degenerative changes in the central nervous system, thereby increasing vulnerability to dementia.

Planting a Flag

Commenting on the report for Medscape Medical News, Keith Fargo, PhD, director of scientific programs and uutreach at the Alzheimer's Association, who was not involved with the research, said that there "was not a lot that's new in this particular study, since it is a compilation of four existing studies, and most of the 30,000 people represented come from a single previous study of 27,000."

Nevertheless, the study "plants a flag and is call to action to the research community, more than to the treatment community," because it "would be good for the clinician community to have solid evidence as to whether treating anxiety in midlife would reduce risk of dementia."

The 10-year "follow-up window" in these studies "would be consistent with the fact that anxiety is an independent risk factor for dementia, but the fly in the ointment is that dementia symptoms set in long after the brain changes that lead to dementia — in the case of Alzheimer's, amyloid plaques can be deposited in the brain as many as 20 years before dementia sets in," Fargo noted.

Midlife anxiety or depression, therefore, "may actually be an early symptom caused by brain changes that eventually manifest as dementia symptoms, so from that perspective, anxiety and depression might be predictive, but it is unknown if they are risk factors and if treating them will reduce risk — this will only be known with clinical trials."

Although screening people in midlife who have anxiety "may seem innocuous, recent recommendations, as with prostate cancer, are to scale back on screening, because benefits are not strong enough to outweigh potential risk of overtreatment," he cautioned.

Marchant agreed that it is currently too soon to suggest routine screening for dementia in middle-aged adults who have anxiety, but she noted that there are evidence-based nonpharmacologic therapies that "already exist to reduce anxiety," so the "next step is to study whether these therapies could also reduce risk for dementia and therefore be offered as preventative therapy."

The research was supported by a grant from the British Geriatrics Society. Dr Marchant was supported by University College London and the Alzheimer' s Society. Dr Marchant's coauthors and Dr Fargo have disclosed no relevant financial relationships.

BMJ Open. Published online April 30, 2018. Full text

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