Clinical Context

Among adults with MCI, 35% to 85% have neuropsychiatric symptoms (NPS), which often occur in early AD and may precede measurable cognitive decline. Apathy is one of the most common NPS in patients with mild cognitive impairment (MCI), often co-occurring with depression and other NPS.

Apathy, defined as reduced self-initiated or environment-stimulated goal-directed behaviors with emotional flattening, affects approximately 11% to 45% of people with MCI. Patients with apathy are more likely to have functional impairment in activities of daily living, independent of age, cognitive function, and depression.

Study Synopsis and Perspective

The presence of apathy may predict conversion from MCI to Alzheimer’s disease (AD), new research suggests.

Investigators followed more than 1000 individuals with MCI over the course of an 8-year period. During that time, close to one fifth converted from MCI to AD. Of those with apathy, 36% developed AD versus 14% of those without apathy. Moreover, conversion to AD was more rapid in those with apathy versus those without a median of almost 4 years compared with a median of almost 7 years.

“The take-home message for clinicians is that apathy is associated with neurodegenerative diseases,” senior author Antonio Teixeira, MD, PhD, professor of psychiatry and head of the neuropsychiatry program, McGovern Medical School, UTHealth, Houston, Texas, told Medscape Medical News.

“If a person starts developing apathy it could either prompt further investigation or at least closer following,” he said.

The study was published online March 7 in the Journal of Alzheimer’s Disease.

Distinct Trajectories

Approximately 80% of patients with MCI go on to develop AD within a 6-year period, the investigators note. “Given the impact of AD, it is paramount to define parameters associated with distinct trajectories of MCI patients, especially identifying those who are more prone to develop AD.”

Dr Teixeira defined apathy as “loss of interest and reduction in goal-directed behaviors.”

NPS are reported in an estimated 35% to 85% of patients with MCI and also are often present in the early stages of AD, preceding the onset of measurable cognitive decline. Previous research suggests that NPS, including apathy, may predict conversion from MCI to dementia.

However, previous research “did not specifically evaluate the role of moderating factors,” such as age or MCI type. Moreover, previous studies have been conducted in primarily non-Hispanic White populations, “limiting the generalizability of the findings.”

The researchers therefore turned to subjects enrolled in the Texas Alzheimer’s Research and Care Consortium (TARCC)--a cohort with a significant percentage of Hispanic participants--to explore conversion rates for MCI to AD and determine the predictive role of apathy in the progression from MCI to AD.

TARCC is a state-funded longitudinal multisite study consisting of a cohort of adults 50 years old or older who are noncognitively impaired, patients with MCI, and patients with AD.

Family members/caregivers completed the Neuropsychiatry Inventory Questionnaire (NPI-Q), and participants underwent a battery of cognitive tests, including the Mini-Mental State Exam (MMSE).

The study included 1092 individuals diagnosed with MCI at any point during the study (59% women; mean [SD] age, 71.8 [standard deviation, 8.61] years; mean years of education, 12.58 [standard deviation, 4.38]). The cohort was evenly divided between Hispanic and non-Hispanic participants.

Of the total cohort, 158 individuals had apathy and 934 did not.

Researchers performed a total of 2897 observations, with the number of observations ranging from 1 to 9 per individual and a median observation count per participant of 2 (interquartile range: 1, 4).

Participants were followed for 8.2 years.

Efficient and Scalable

During the study period, 17.3% of participants experienced conversion from MCI to AD across all observations, with a median time to conversion of 6.4 years.

Researchers stratified the severity of apathy using a 4-level index, beginning with “no apathy” and going through “mild,” moderate,” and “severe” apathy. The presence of apathy was significantly related to the outcome, with the relationship increasing in tandem with greater severity (Table 1).

Table 1. Apathy Severity and Relationship to Outcome

Moderation models found that age had a significant moderating effect (adjusted P=.002). For those who had apathy, the relationship between age and time to conversion was “essentially null.” However, for those without apathy, there was a 5% increase in the hazard of conversion per additional year of age (P<.001).

In adjusted and unadjusted models, MMSE score showed a moderating effect (P<.001), but the effect was stronger in those with versus without apathy (hazard ratio, 0.75 vs 0.87, respectively; both P<.001).

“Our results showed that MCI patients with apathy have significantly higher conversion rates to AD compared with MCI patients without apathy, even after adjustment for confounding factors,” the investigators write.

Dr Teixeira noted that there is “overlap” between depression and apathy, but not all people with depression experience apathy, and all apathy is not necessarily related to depression, “which is why we controlled for depression.”

He observed that many clinicians treat patients with apathy by prescribing antidepressants. “But the apathy may not necessarily be associated with depression, and antidepressants might even make it worse. It’s important to tease out apathy from depression,” he said.

Assessing apathy may be an “efficient and highly scalable method for improving risk stratification across clinical and research settings,” the researchers note.

One of Many Factors

Commenting on the study for Medscape Medical News, Claire Sexton, DPhil, senior director of scientific programs and outreach, Alzheimer’s Association, said: ”A strength of this research is that the study population is significantly more diverse than previous work on this topic.”

However, “the study also has a number of limitations, including short follow-up time and diagnosis that did not include measurement of key biomarkers; therefore, for these findings to have a high level of credibility they need to be replicated in more rigorous studies,” said Dr Sexton, who was not involved with the study.

“Based on the totality of research, it is still very likely that apathy is only one of many factors that influence the rate of progression from MCI to Alzheimer’s dementia,” she added.

She noted that the Alzheimer’s Association “believes that it is important for clinicians--and family caregivers--to monitor for and manage behavioral and neuropsychiatric symptoms, including apathy, throughout the disease course,” which “can be an important part of maintaining or improving everyone’s quality of life.”

This study was supported by the Texas Alzheimer’s Research and Care Consortium. Dr Teixeira, other study authors, and Dr Sexton have reported no relevant financial relationships.

J Alzheimers Dis. Published online March 7, 2023.^[1]

Clinical Implications

• NPS, particularly apathy, are associated with MCI to AD progression.
• Apathy assessment might improve risk prediction and targeted intervention delivery.
• Implications for the Health Care Team: Clinicians and caregivers should monitor apathy throughout the disease course, to help maintain quality of life.

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