Plasma P-Tau181 and Neuropsychiatric Symptoms in Preclinical and Prodromal Alzheimer Disease.

• Plasma p-tau181, a well-validated marker of Alzheimer's disease (AD) pathological change, could be a more efficient way to diagnose AD than invasive or expensive biomarkers requiring cerebrospinal fluid or positron emission tomography. 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 suffered from imprecision in capturing behavioral symptoms that represent sequalae 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 six months. Here, cross-sectionally and longitudinally, we investigated associations of MBI with p-tau181, neuropsychological test performance, and incident AD.Cognitively unimpaired and mild cognitive impairment (MCI) Alzheimer 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-one visits were used to operationalize MBI (score>0 at both visits), NPS not meeting MBI criteria (NPS-not-MBI, score>0 at only one 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 longitudinal associations of MBI with changes in p-tau181 and cognition, and incident dementia.The sample included 571 participants (age 72.2, 46.8% female, 64.8% MCI). Cross-sectionally (Beta=8.1%, 95%CI:1.4%-15.2%, p=0.02) MBI was associated with higher plasma ptau-181 levels compared to no-NPS; NPS-not-MBI was not. Longitudinally, MBI was associated with higher p-tau181 (Beta=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.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.

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MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

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