Risk of Incident Dementia Influenced by Apathy, Cognitive Status, and APOE Genotype in Mild Behavioral Impairment


Effect modification by cognitive status and APOE genotype revealed greater effects of mild behavioral impairment with apathy in those who had normal cognition or in non-APOE ɛ4 groups.

Zahinoor Ismail, MD, FRCPC, neuropsychiatrist, University of Calgary

Zahinoor Ismail, MD, FRCPC

Following a cohort of dementia-free participants from the National Alzheimer Coordinating Center, findings showed that the presence of apathy in those with mild behavioral impairment (MBI) increases the risk of progression rate to dementia, with effects modified by cognitive status and apolipoprotein (APOE) genotype.1

All told, those with MBI and apathy had a 2.69- and 2.61-fold greater progression to dementia compared with those who had no neuropsychiatric symptoms (no-NPS) and no apathy, respectively. Senior investigator Zahinoor Ismail, MD, FRCPC, neuropsychiatrist, University of Calgary, and colleagues concluded that this group may "represent a precision medicine target to explore dementia prevention interventions."

Presented at the 2022 Alzheimer’s Association International Conference (AAIC), July 31 to August 4, in San Diego, California, the study included 3932 participants, of whom 354 had MBI-apathy. The study had several aims, including exploring MBI-apathy as a risk factor for incident dementia, investigating the role of APOE in modifying the association between MBI-apathy and incident dementia, and examining the neuroprotective role of APOE ɛ2 in MBI-apathy associated dementia risk.

Results showed that not only did the MBI-apathy group have a greater progression rate to dementia than no-NPS (hazard ratio [HR], 2.69; 95% CI, 2.15-3.36; P <.001), but that the interaction effects were moderated by cognitive diagnosis and APOE genotype. In the secondary analysis, Cox regressions determined HRs of progression to dementia for MBI-apathy relative to no-apathy, adjusted for baseline age, sex, years of education, race, cognitive diagnosis, and APOE genotype.

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Among those who had NPS, the HR for risk to dementia was greater in individuals with normal cognition (NC; HR, 5.91; 95% CI, 95% CI, 3.91-8.93) compared with those with mild cognitive impairment (HR, 2.16; 95% CI, 1.69-2.77). Between APOE genotypes, the HR was greater for those with ɛ3 alleles (reference; HR, 4.25; 95% CI, 3.10-5.82) vs ɛ4 (HR, 1.81; 95% CI, 1.32-2.47), but not significantly greater for ɛ3 vs ɛ2 (HR, 4.26 [95% CI, 3.10-5.82]; vs HR, 2.6 [95% CI, 1.2-5.6]) or ɛ2 vs ɛ4 (HR, 2.6 [95% CI, 1.2-5.6]; vs HR, 1.81 [95% CI, 1.32-2.47]).

"Understanding the interaction between genetic, behavioral, and cognitive risk factors of AD is essential in determining preventative interventions for the development of AD dementia,” Ismail et al concluded.1

In 2021, a systematic review and meta-analysis of 10 studies comprising 26,195 individuals was published, examining the association between apathy and the transition from normal cognitive function to cognitive impairment and dementia. Apathy status, available for 22,101 participants, was present in 8.16% (n = 1803) of those, with follow-up ranging from 1 to 13 years. Results showed that apathy was associated with a greater than 2-fold increased risk of progression to cognitive impairment in the cognitively normal population.

Additional details from the study revealed a combined odds ratio [OR] or 2.07 (95% CI, 1.43-2.99; I2 = 86%) and HR of 2.70 (95% CI, 1.38-5.27; I2 = 94%) for cognitive impairment for patients with apathy, The OR meta-analyses for difference conversion outcomes were MCI (OR, 3.38; 95% CI, 1.57-7.28; I2 = 71%), cognitive decline (OR, 1.27; 95% CI, 0.81-2.00; I2 = 64%) and dementia (OR, 2.12; 95% CI, 1.32-3.41; I2 = 86%). Subgroup analyses suggested that the association between apathy and cognitive impairment changed with age, depression adjustments, apathy measurement, and follow-up time.2

Click here for more coverage of AAIC 2022.
1. Vellone D, Ghahremani M, Ismail Z. Apathy and APOE e2 in mild behavioral impairment, and risk for Alzheimer disease dementia. Apathy in mild behavioral impairment is associated with incident dementia. Presented at: 2022 Alzheimer’s Association International Conference; July 31-August 4; San Diego, CA. 59666
2. Fan Z, Wang L, Zhang H, et al. Apathy as a risk neuropsychiatric syndrome of progression from normal aging to mild cognitive impairment and dementia: a systematic review and meta-analysis. Front Psychiatry. 2021;12:792168. doi:10.3389/fpsyt.2021.792168
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