Genetic risk for Alzheimer disease, cognition and Mild Behavioral Impairment in healthy older adults

Abstract

BACKGROUND: Mild Behavioral Impairment (MBI) is a neuropsychiatric syndrome describing later-life emergent apathy, mood/anxiety symptoms, impulse dyscontrol, social inappropriateness and psychosis that are not attributable to psychiatric diagnoses. MBI is an at-risk state for incident cognitive decline and dementia, and is associated with dementia biomarkers including amyloid beta; and neurofilament light. Thus, MBI may be an early clinical marker of neurodegenerative disease. In this study, we hypothesized that stratification by MBI in a cognitively normal sample would moderate the signal between Alzheimer disease (AD) genetic risk and cognition. METHODS: Genetic, cognitive and MBI data was available for 3,126 PROTECT study participants over 50 without dementia. A general cognitive composite score was constructed based on scores on paired associates learning, digit span, self-ordered search and verbal reasoning. MBI was assessed using the MBI Checklist. Polygenic scores for AD were split by tertile (representing low, medium and high risk) and the sample was stratified by MBI into those with no symptoms and those with any symptoms. RESULTS: AD genetic risk was associated with poorer cognition in the MBI strata only (MBI: F(2,1746)=4.95, p=0.007; no MBI: F(2,1366)=0.72, p=0.49). The mean difference between low and high genetic risk groups was significant (p=0.005) and the standardised effect size in the MBI sample was higher than in the whole sample. CONCLUSIONS: These findings justify MBI screening to enrich samples with at-risk individuals, and underscore the importance of late-life neuropsychiatric symptoms in cognitive ageing.

Prevalence of mild behavioural impairment: a systematic review and meta‐analysis

“…Another two studies were excluded from the meta‐analysis because their populations overlapped with those of previous studies, but they were suitable for systematic review (Table S1). 20, 21 …”

“…With regard to the defining criteria for MBI, six studies used the Neuropsychiatric Inventory Questionnaire, three studies used the ISTAART criteria, and two studies used MBI‐C (Table 1). Thirteen studies were included in the systematic review to examine the effect of MBI in predicting cognitive deterioration, correlations to underling pathology or biomarkers, and genetic risks 20, 22–33 . No previous systematic review or meta‐analysis was identified.…”

Mild behavioral impairment is related to frailty in non-dementia older adults: a cross-sectional study

“…Although MBI and MCI can co-occur, MBI can also precede MCI, manifesting in older adults with subjective cognitive decline or even normal cognition, in whom MBI has demonstrated an increased risk of cognitive decline and dementia [22][23][24][25][26]. MBI may be the initial manifestation of neurodegeneration for some, and has been connected with known biomarkers for dementia including amyloid beta [27], tau [28,29], neurofilament light [30], cortical atrophy [31,32], white matter atrophy [33], and AD risk genes [34,35]. MBI has also been used in machine learning models to predict neurocognitive diagnostic category 40 months later [36].…”

Mild behavioral impairment is related to frailty in non-dementia older adults: a cross-sectional study

“…Although MBI and MCI can co-occur, MBI can also precede MCI, manifesting in older adults with subjective cognitive decline or even normal cognition, in whom MBI has demonstrated an increased risk of cognitive decline and dementia (22)(23)(24)(25)(26). MBI may be the initial manifestation of neurodegeneration for some, and has been connected with known biomarkers for dementia including amyloid beta (27), tau (28,29), neuro lament light (30), cortical atrophy (31,32), white matter atrophy (33), and AD risk genes (34,35).…”