Plasma Phosphorylated Tau at Threonine 181 and Neuropsychiatric Symptoms in Preclinical and Prodromal Alzheimer Disease

Abstract

Background and objectives: Plasma phosphorylated tau at threonine 181 (p-tau181), a well-validated marker of Alzheimer disease (AD) pathologic change, could be a more efficient way to diagnose AD than invasive or expensive biomarkers requiring CSF or PET. In some individuals, neuropsychiatric symptoms (NPS) are the earliest manifestation of AD, observed in advance of clear cognitive decline. However, the few studies assessing AD biomarkers in association with NPS have often had imprecision in capturing behavioral symptoms that represent sequelae of neurodegenerative disease. Thus, the mild behavioral impairment (MBI) construct was developed, framing NPS in a way to improve the precision of risk estimates for disease. MBI core criteria stipulate that NPS emerge de novo in later life and persist for at least 6 months. Here, cross-sectionally and longitudinally, we investigated associations of MBI with p-tau181, neuropsychological test performance, and incident AD.

Methods: Cognitively unimpaired and mild cognitive impairment (MCI) Alzheimer's Disease Neuroimaging Initiative participants were selected. MBI status was derived from the Neuropsychiatric Inventory (NPI) using a published algorithm. NPI total scores at baseline and year 1 visits were used to operationalize MBI (score >0 at both visits), NPS not meeting the MBI criteria (NPS-not-MBI, score >0 at only 1 visit), and no NPS (score = 0 at both visits). Linear regressions were fitted for cross-sectional analyses; multilevel linear mixed-effects and Cox proportional hazards models were implemented to examine the longitudinal associations of MBI with changes in p-tau181 and cognition and incident dementia.

Results: The sample included 571 participants (age 72.2 years, 46.8% female, 64.8% MCI). Cross-sectionally (β = 8.1%, 95% CI 1.4%-15.2%, p = 0.02), MBI was associated with higher plasma p-tau181 levels compared with no NPS; NPS-not-MBI was not. Longitudinally, MBI was associated with higher p-tau181 (β = 0.014%, 95% CI 0.003-0.026, p = 0.02), in addition to a decline in memory and executive function. Survival analyses demonstrated a 3.92-fold greater dementia incidence in MBI, with no significant differences between NPS-not-MBI and no NPS.

Discussion: These findings extend the evidence base that MBI is associated with elevated risk of cognitive decline and dementia and a sequela of emerging Alzheimer-related proteinopathies. MBI offers a substantial improvement over current approaches that explore behavior as a proxy marker for Alzheimer-related proteinopathies, with both clinical and AD trial enrichment implications.

Figure 1. Flowchart Illustrating the Step-by-Step Process of Inclusion/Exclusion Criteria of the Present Study

ADNI = Alzheimer's Disease Neuroimaging Initiative; CU = cognitively unimpaired; MBI = mild behavioral impairment; MCI = mild cognitive impairment; NPI = Neuropsychiatric Inventory; NPI-Q = Neuropsychiatric Inventory Questionnaire; NPS = neuropsychiatric symptoms.

Figure 2. Violin Plot of the Distribution of Unadjusted Log-Transformed Plasma p-tau181 Values at Baseline Across NPS Categories

In each NPS category, gray dots represent individual data points of log-transformed p-tau181 values, and the embedded box plot in blue represents the median, 25th, and 75th percentiles. MBI = mild behavioral impairment; NPS = neuropsychiatric symptoms.

Figure 3. Kaplan-Meier Survival Curves and Adjusted Hazard Ratios for Dementia Across NPS Categories

(A) Dementia-free survival curves across NPS categories: no NPS, NPS-not-MBI, and MBI. (B) Forest plot of adjusted hazard ratios for dementia across NPS categories. Error bars represent the 95% CIs. MBI = mild behavioral impairment; MMSE = Mini-Mental State Examination; NPS = neuropsychiatric symptoms.