High Amyloid, Anxiety, Depression May Predict Early Alzheimer's

Batya Swift Yasgur, MA, LSW

January 22, 2018

High levels of amyloid beta combined with symptoms of anxiety and depression that increase over time may signal preclinical Alzheimer's disease (AD), new research suggests.

"It has been well established that people with neuropsychiatric symptoms are twice as likely to progress to the mild cognitive impairment phase of Alzheimer's disease over the course of the next 3 to 6 years and that somehow, these neuropsychiatric symptoms are involved with the process of progression," lead author Nancy J. Donovan, MD, associate psychiatrist, Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, and assistant professor of psychiatry, Harvard Medical School, Boston, Massachusetts, told Medscape Medical News.

"Our standing quest is to find out whether it is a parallel process or whether Alzheimer's disease biomarkers are involved, and this is a first step in establishing that there is a biological connection between amyloid and, in this case, symptoms of anxiety," she said.

The study was published online January 12 in the American Journal of Psychiatry.

Earliest Manifestations

"Alzheimer's disease begins with a long 'preclinical' phase defined by the accumulation of brain deposits of fibrillar amyloid and pathological tau," the authors write.

Observational studies have implicated neuropsychiatric symptoms such as depression as predictors of AD progression during this preclinical period, even in cognitively normal people.

Previous studies have suggested that cognitively normal older individuals with biomarker evidence of amyloidosis are more likely to experience increasing symptoms of depression over time.

"At the same time, these preliminary observations raise more pointed questions as to the quality, severity, and time course of depressive symptoms that are most characteristic of preclinical Alzheimer's disease and the specificity of their associations with Alzheimer's molecular markers," the investigators note.

To investigate this question, the researchers studied the relationship between cortical aggregate amyloid beta and longitudinal measures of depression in a cohort of cognitively normal older adults whose levels of amyloid beta varied widely. The study participants included a subset of persons with amyloid beta levels consistent with preclinical AD.

"We are very interested in understanding the earliest possible manifestations of AD in people who do not yet have frank cognitive impairment because we think we will be able to identify people at high risk, based on a combination of biological and clinical markers," Dr Donovan said.

The researchers used data from the Harvard Aging Brain Study. The cohort consisted of 270 cognitively normal community-dwelling men and women (aged 62 to 90 years) who did not have major psychiatric disorders at the time of involvement. The participants completed study visits during a 5-year period (mean number of visits, 3.8).

Individuals were allowed to participate in the study if they had a history of past or current depression, provided their depression was adequately treated with standard antidepressant medication. All participants scored below the cutoff score (≥11) on the 30-item Geriatric Depression Scale (GDS).

Cognitive status was determined using the Clinical Dementia Rating scale, the Wechsler Memory Scale, and the Mini–Mental State Examination.

In addition, participants underwent baseline clinical assessments with the American National Reading Test (AMNART), a measure of premorbid intelligence, and the two-factor Hollingshead score, calculated according to primary occupation and educational attainment.

Pittsburgh compound B (PiB) positron-emission tomography was used to measure fibrillar amyloid burden. The assessment included a single region representing the aggregate cortical areas at risk for amyloid burden across the frontal, lateral temporal, and lateral and medial parietal lobes.

At baseline, the mean GDS score was 2.8 for the entire sample and 3.7 for participants with a history of depression.

The average scores were greater for the apathy-anhedonia and anxiety concentration clusters than for the dysphoria cluster (mean values, 0.161, 0.129, and 0.030, respectively).

PiB binding was not significantly correlated with any of the GDS scores at baseline.

Amyloid, Neuropsychiatric Symptoms Linked

Thirteen percent of study participants reported a history of depression; 7% reported current depression (active depression) within 2 years of enrollment; and 6% reported past depression but no active depression within 2 years of enrollment (past depression).

Participants did not differ proportionally across sex or APOEε4 categories, regardless of depression status.

The researchers found a significant difference in mean PiB binding between participants who did not have a history of depression, compared to those with current depression (1.16 and 1.28, respectively; P = .006), but not compared to those with past depression (1.16 and 1.22, respectively; P = .2).

In the final model of GDS score used, the adjusted mean GDS score over time was found to be higher for participants with a history of depression than for those who did not report depression.

In that model, the interaction of PiB binding with time was also a significant predictor; higher baseline PiB binding was associated with steeper increases in GDS score over time.

APOEε4 and its interaction with time were not associated with higher GDS score, and no other fixed terms were significant.

The researchers conducted a post hoc analysis in which anxiety-only scores were analyzed by excluding concentration disturbance items. They found that effects were virtually the same — ie, the PiB binding-by-time interaction remained significant.

Beyond the main effect of depression history, lower AMNART score, which was a measure of premorbid intelligence, was also associated with steeper increases in anxiety-concentration score over time.

Dr Donovan said she was not surprised by the findings "because there have been suggestions in the literature that certain neuropsychiatric symptoms may be more common and more associated with amyloid than others."

She cited a previous study conducted by her group that demonstrated an association between amyloid and symptoms of loneliness.

"Certain types of symptoms seem to go together, and it is possible that as people start to decline, they become more anxious and may also start to socially withdraw, which could be early warning signs of a pathological process," she suggested.

"Since amyloid accumulates in the brain over at least 10 years prior to prodromal AD or actual cognitive impairment, there are probably many dynamic changes occurring in the brain in response to the amyloid accumulations," she said.

New-Onset Anxiety Suspicious

Commenting on the study for Medscape Medical News, Ronald Petersen, MD, PhD, professor of neurology, Mayo Clinic College of Medicine, and director, Mayo Clinic Alzheimer's Disease Research Center, Rochester, Minnesota, who was not involved with the study, called the findings "interesting, although not absolutely unique, since others have been looking at these issues as well."

He noted that participants in the study were generally high functioning, highly educated, and of higher socioeconomic status and occupational attainment, "so they may be more in tune and sensitized to their own feelings of dysphoria or anxiety, which may give slightly different measurements on instruments as compared to other people."

Although this observation "does not negate the results, it does put a cautionary note on generalizability," he said.

The study findings are important, however, and "should alert PCPs [primary care physicians] to the potential implications of more subtle, affective symptoms of depression, anxiety, or apathy in people in later life, although it may be more difficult to interpret in those with a lifelong history of depression or anxiety," he said.

He cautioned that even in new-onset late-life depression, "people are going through life changes, such as retiring or losing spouses, so being sad, discouraged, or blue does not necessarily mean that they have extra amyloid in their brains."

Dr Donovan added that about 30% of older people who are not depressed have significant symptoms of anxiety, but only a small proportion have underlying AD.

"But if someone is presenting with new anxiety and subjective or frank changes in memory or cognitive function, that raises the level of suspicion that there could be a neurodegenerative process such as AD, not only normal aging," she said.

The study was supported by the National Institute on Aging, the Harvard Medical School Department of Psychiatry Dupont-Warren Fellowship and Livingston Award, the Rogers Family Foundation, the Massachusetts Alzheimer's Disease Research Center, and the Harvard Aging Brain Study. Dr Donovan has received salary support from Eisai and Eli Lilly; her spouse is employed by Alkermes. The other authors' relevant financial relationships are listed in the original article.

Am J Psychiatry. Published online January 12, 2018. Abstract

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