Apathy Linked to Amyloid Deposition

Higher initial amyloid levels in certain brain regions of older adults with no cognitive or psychiatric symptoms at baseline are associated with greater informant-rated but not self-rated apathy at long-term follow-up.

Understanding the biologic underpinnings of apathy could help identify those who might benefit from anti-amyloid therapy earlier on, study investigator Catherine Munro, PhD, a clinical neuropsychologist and instructor in neurology, Harvard Medical School, and Brigham and Women’s/Mass General, Boston, told Medscape Medical News.

“If someone’s showing maybe some very mild cognitive symptoms but a lot of behavioral symptoms that could align with amyloid deposition in certain areas of the brain, they may benefit from an anti-amyloid therapy,” she explained.

The findings were presented July 29 at the Alzheimer’s Association International Conference (AAIC) 2024. 

An Early Sign of Alzheimer’s Disease? 

Apathy is a complex psychiatric symptom that reflects a lack of interest, motivation, or enjoyment of things that are normally pleasurable.

Rates of apathy are high in Alzheimer’s disease (AD). Even among those with subjective cognitive decline, about 40% have symptoms of apathy. “And these rates only increase as we move forward to cognitive impairment and dementia syndrome,” said Munro.

The investigators have previously shown that increased amyloid in brain areas of emotional control is associated with elevated levels of depression, independent of cognitive decline. They were keen to determine if there are similar regional relationships between cortical amyloid levels and apathy.

The study included 199 participants from the Harvard Aging Brain Study, the mean age was 79.9 years, 61.3% were women, and 81.9% were White. At study outset, participants had no significant cognitive or psychiatric impairment. In addition, all had a study partner who served as an informant. 

Participants completed the 18-item Apathy Evaluation Scale (AES), which is specifically designed to measure apathy in older adults. It has a total score of 18-72, with lower scores indicating greater apathy. Study participants and their partners completed this assessment separately.

Researchers performed PET imaging using Pittsburgh Compound B (PIB) to determine amyloid levels in regions of interest. These included the inferior temporal (IT), entorhinal, precuneus, supramarginal, anterior cingulate (ACC), medial orbitofrontal (mOFC) , lateral orbitofrontal cortices, amygdala, and thalamus.

Munro noted the study used regional amyloid measurements, “as opposed to global cortical aggregates that are often used in AD studies. “Investigators controlled for age, sex, education, and time-to-follow-up, and adjusted P values for multiple comparisons.

Baseline amyloid was associated with lower informant-rated AES score (greater apathy) at follow-up (8 years) in the IT (adjusted P =.009), precuneus (P =.005), supramarginal (P =.007), ACC (P =.005), and mOFC (P =.006) regions.

Baseline PIB did not predict self-rated AES score at follow-up in any of the regions examined.

“When people were not cognitively impaired, if they had amyloid in certain key regions associated with apathy, they had more informant ratings of apathy later on,” said Munro.

Not all brain regions were correlated with informant-reported apathy. Munro suspects this may just be that some brain areas are less susceptible to amyloid accumulation.

“We don’t tend to see as much amyloid accumulation in subcortical areas like the amygdala or thalamus; we still looked at those regions, but we didn’t see any signal there.”

The research is informative about the neurobiology of behavioral symptoms, said Munro. “We’re seeing some regional patterns to amyloid deposition, where amyloid in certain areas of the brain is related to things like emotional control, depression, and apathy.”

Behavioral symptoms might be a psychological reaction to having a very traumatic disease like AD. 

“People certainly may feel more apathetic, or they may feel more depressed or anxious if they learn that they have such a disease,” said Munro.

And as the disease progresses, there might be more severe symptoms, for example, more severe apathy, delusions, or hallucinations, she added. 

“But I think the field is now moving towards recognizing that even very early in the disease, you can see symptoms like depression, anxiety, and apathy that might have a biological basis rather than being a psychological reaction.” 

Research on apathy and amyloid is a new research frontier, said Munro. The term mild behavioral impairment or MBI is being tossed around and apathy is “a sort of a behavioral analog to mild cognitive impairment,” she added.

The research suggests that in some people, early behavioral symptoms may present before objective cognitive impairment or dementia. Reducing apathy improves quality of life not only for patients but also their caregivers. “Often, apathy is one of those symptoms that bothers the caregivers more than it bothers the patient themselves,” said Munro.

It’s critical that the relationship between apathy and amyloid “are examined in larger samples of more racially and ethnically diverse individuals that span different cultural and geographic regions,” said Munro. 

The Value of Partner Reports

Commenting on the research for Medscape Medical News, Christopher Weber, PhD, Alzheimer’s Association director of global science initiatives, said the findings are “potentially informative of the disease trajectory of Alzheimer’s and the relationship based on formation of amyloid plaques.”

Additional data are needed from a more diverse cohort “before applying these findings to the general population,” said Weber.

He said he would be interested in knowing whether amyloid or other AD hallmarks show similar trends with other neuropsychiatric symptoms associated with those living with the disease.

Also commenting for Medscape Medical News, Klodian Dhana, MD, PhD, associate professor, Department of Internal Medicine, Division of Geriatrics and Palliative Medicine, Rush University, Chicago, Illinois, said the study highlights the importance of partner reports.

“Recognizing that apathy is associated with a higher risk of dementia, this study underscores the importance of involving study partners to capture signs and symptoms related to apathy.”

No relevant conflicts of interest were reported.