Apathy and Affective Symptoms Associated with Elevated Alzheimer’s Disease Biomarkers

Importance While apathy and affective neuropsychiatric symptoms (NPS) are common in the clinical spectrum of Alzheimer’s disease (AD), their neurobiological correlates remain unclear. Objective To longitudinally examine plasma markers of neurodegeneration (neurofilament light chain; NfL) and tau pathology (phosphorylated at threonine 181; p-tau181) and their associations with apathy and affective symptoms in individuals with clinical diagnoses of AD dementia and mild cognitive impairment (MCI). Design, Setting, Participants and Exposure This cohort study used longitudinal data from the Alzheimer Disease Neuroimaging Initiative (ADNI). Individuals with clinical diagnoses of MCI and AD dementia were enrolled in ADNI with serial annual blood samples over a four-year period, which were analyzed for NfL and p-tau181 using ultrasensitive techniques. Study data were accessed between July and September 2024. Main Outcomes and Measures The presence of neuropsychiatric symptoms was determined using the Neuropsychiatric Interview (NPI). We analyzed the trajectory of plasma NfL and p-tau181 in each NPS using general linear mixed-effects models adjusted for age and sex. Results There were 790 participants with AD dementia and MCI (mean [SD] age 72.7 [7.6] years; 333 females, 42%) and 417 healthy controls. The most common NPS was depression (n = 428; 54%), followed by irritability (n = 419; 53%), apathy (n = 348; 44%) and anxiety (n = 341; 43%). In the AD dementia and MCI group, apathy and anxiety were associated with higher levels of both NfL and p-tau181 after controlling for cognitive and functional decline. Moreover, apathy was associated with higher rate of NfL increase longitudinally. Depression at baseline was initially associated with higher NfL and p-tau181 levels, but this did not remain significant in the sensitivity analyses. Conclusion and Relevance This study found that in individuals with clinical AD, apathy and anxiety are associated greater tau and neurodegenerative burden. Furthermore, those with apathy had a higher rate of NfL increase, which suggests an accelerated neurodegenerative process. These findings highlight that these symptoms be indicative of AD pathology severity and have implications for potential treatments which target tau pathology. Key Points Question Do apathy and affective neuropsychiatric symptoms correlate with the rate of tau pathology and neurodegeneration, as measured by plasma phosphorylated-tau181 (p-tau181) and neurofilament light chain protein (NfL), in individuals across the clinical spectrum of Alzheimer’s disease (AD)? Findings: In a longitudinal study of 790 patients with mild cognitive impairment (MCI) and AD dementia, serial measurements of plasma p-tau181 and NfL were collected annually over four years. P-tau181 and NfL levels were elevated in those with apathy or anxiety compared to those without. The rate of NfL increase, an indicator of neurodegeneration, was significantly higher in those with apathy. Meaning The presence of anxiety and apathy was associated with elevated biomarkers of neurodegeneration in MCI and AD dementia. Notably, apathy was linked to a faster rate of NfL increase, suggesting an accelerated neurodegenerative process.