Agitation, psychosis and depression are among the more harrowing symptoms of Alzheimer’s disease, and also the most challenging to treat.

Medications prescribed to alleviate these neuropsychiatric symptoms sometimes work and sometimes don’t. That’s because clinicians repurpose treatments meant for psychiatric populations, without taking into account the underlying mechanisms that are causing the symptoms in patients with Alzheimer’s disease.

A literature review led by Milap Nowrangi, assistant professor of psychiatry and behavioral sciences at Johns Hopkins, addresses this problem by examining the biological causes of depression, psychosis and agitation in patients with Alzheimer’s disease. Eventually, it could lead to treatments that are better tailored to individual patients.  

Co-authors for the systematic review, Neuropsychiatric Symptoms of Alzheimer’s Disease: An Anatomic-Genetic Framework for Treatment Development, include Constantine Lyketsos, director of the Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease, and Richman Center and psychiatry colleagues Dimitrios Avramopoulos and Paul Rosenberg.

“It is hoped that understanding the dynamic between genes and structure will aid the development of targeted and individualized therapies for symptoms such as depression, psychosis and agitation and aggression of AD,” the paper notes.

Nowrangi is on the faculty of the Richman Center, which, like other disease-focused precision medicine centers of excellence at Johns Hopkins, uses large amounts of data to better understand an individual’s disease variations and trajectory. For Alzheimer’s disease, researchers are studying family histories, medical records, brain images and genetic codes to gain new insights into a historically opaque condition. 

For example, Roy Adams, assistant professor of psychiatry and behavioral sciences, is using data from more than 140,000 medical records to predict dementia progression as many as three years into the future. “The ultimate goal is to unite as many of these types of data as we can to say as much as we can about why each patient presents differently,” Adams says.

While amyloid buildup in the form of plaques and neurofibrillary tangles in the brain remain important indicators of Alzheimer’s disease, they do not fully explain the variabilities in the disease and its symptoms, says Lyketsos, adding that amyloid-clearing medications that recently won FDA approval do little to alleviate symptoms.

“We’re recognizing that for folks with a clinical diagnosis of Alzheimer’s, the removal of amyloid only modestly helps them,” he says. “One line of thought is that amyloid is important, but the fraction of symptoms due to amyloid is not very big.”

In his literature review, Nowrangi looked at both genetic and imaging studies of patients with Alzheimer’s disease. “The paper is really trying to identify the underlying biological mechanisms that we ought to look at that take advantage of our knowledge of brain structure, function and chemistry and the genes behind all of those symptoms,” he says.

Among its findings, the paper describes overlap between atrophy in specific brain lobes and genes that code for monamine neurotransmitters such as dopamine or serotonin. For example, patients with Alzheimer’s disease and psychotic symptoms such as delusions or paranoia often exhibit atrophy of the temporal and parietal lobes, and anomalies in genes that code for serotonin synthesis and function.

Better understanding could lead to better use of existing therapies, as well as development of new ones, says Nowrangi.

“That’s kind of the dream, that when a patient comes in who has Alzheimer’s disease and has a neuropsychiatric symptom, we can say, ‘OK, we’re going to treat your depression as part of your Alzheimer’s with this medication that’s directly focused at the mechanisms that we believe are causing your depression.”