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

Abstract

Objective: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 emergede novoin 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.Methods: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.Results: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.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.

Late‐life onset psychotic symptoms and incident cognitive impairment in people without dementia: Modification by genetic risk for Alzheimer's disease

“…In this regard, finding that one symptom of a neurodegenerative disease predicts another would be unsurprising but to definitively show this requires imaging and biomarker studies that can determine etiology. [33][34][35][36][37][38] Our findings provide a clear rationale for such studies.…”

“…However, implied within our hypotheses is that, for some, both MBI‐psychosis and the cognitive endpoint of IQCODE >3.6 are sequelae of a common underlying neurodegenerative disease. In this regard, finding that one symptom of a neurodegenerative disease predicts another would be unsurprising but to definitively show this requires imaging and biomarker studies that can determine etiology 33–38 . Our findings provide a clear rationale for such studies.…”

Apathy and APOE in mild behavioral impairment, and risk for incident dementia

“…This has previously been demonstrated in samples of NC, subjective cognitive impairment, and MCI, where applying MBI criteria demonstrated better specificity for AD detection and dementia prognostication compared to conventional approaches to assessing NPS. 2 , 23 Nonetheless, these findings have implications for the importance of behavioral symptoms in predicting future dementia prior to cognitive symptom onset, offering a window of opportunity for treatment at an early stage of the disease.…”

“…Second, we investigated the associations between MBI-apathy status and dementia incidence but cannot assume causation. Future studies may benefit from investigating AD biomarkers 23,[38][39][40] and regionspecific neurodegenerative markers 5,41,42 in combination with AD genetic risk 43,44 to explore further if MBI-apathy is an independent risk factor or an early disease marker. 45 Future studies may benefit from investigating apathy severity, to provide a more complete understanding of this association.…”

Contribution of amyloid and putative Lewy body pathologies in neuropsychiatric symptoms

“…11 MBI detected in the affective dysregulation domain tends to increase the risk of conversion of MCI to dementia, especially AD. 4 Many studies have reported on the relationship between MBI and AD biomarkers, such as beta-amyloid [12][13][14][15] and tau, [15][16][17] and Alzheimer's genetic loci. 18,19 Neuroimaging studies of MBI indicate an association with the brain regions related to AD, 20 including medial temporal lobe atrophy, 9,21,22 default mode network, 23 and frontoparietal control network dysfunction.…”