Association of Alzheimer's genetic loci with mild behavioral impairment

Abstract

Mild behavioral impairment (MBI) describes the emergence of later-life neuropsychiatric symptoms (NPS) as an at-risk state for incident cognitive decline and dementia, and for some as a potential manifestation of prodromal dementia. How NPS mechanistically link to the development of mild cognitive impairment and Alzheimer's disease (AD) is not fully understood, with potential mechanisms including shared risk factors related to both NPS and cognitive impairment, or AD pathology promoting NPS. This is the first exploratory study to examine whether AD genetic loci as a genetic risk score (GRS), or individually, are a shared risk factor with MBI. Participants were 1,226 older adults (aged 72-79; 738 males; 763 normal cognition) from the Personality and Total Health Through Life project. MBI was approximated in accordance with Criterion 1 of the ISTAART-AA diagnostic criteria using a transformation algorithm for the neuropsychiatric inventory. A GRS was constructed from 25 AD risk loci. Binomial logistic regression adjusting for age, gender, and education examined the association between GRS and MBI. A higher GRS and APOE*ε4 were associated with increased likelihood of affective dysregulation. Nominally significant associations were observed between MS4A4A-rs4938933*C and MS4A6A-rs610932*G with a reduced likelihood of affective dysregulation; ZCWPW1-rs1476679*C with a reduced likelihood of social inappropriateness and abnormal perception/thought content; BIN1-rs744373*G and EPHA1-rs11767557*C with higher likelihood of abnormal perception/thought content; NME8-rs2718058*G with a reduced likelihood of decreased motivation. These preliminary findings suggest a common genetic etiology between MBI and traditionally recognized cognitive problems observed in AD and improve our understanding of the pathophysiological features underlying MBI. K E Y W O R D SAlzheimer's disease, genetic risk score, MBI

Prevalence of Mild Behavioral Impairment and Risk of Dementia in a Psychiatric Outpatient Clinic

“…Additionally, in a large community sample of cognitively unimpaired participants, MBI demonstrated an associated with faster decline in attention and working memory [16]. Recent genetic evidence has also demonstrated a common etiology between MBI and AD, suggesting that neurodegeneration may contribute to the emergence of neuropsychiatric symptoms, as it does with emergent neurocognitive symptoms [17]. Case ascertainment for MBI has been operationalized with the MBI checklist (MBI-C, available at http://www.MBItest.org) [18], a rating scale that accurately reflects the MBI criteria with respect to the MBI domains, requirement of symptoms to be of 6 months duration (thus decreasing false positives from reactive states and fluctuating symptoms), explicitly mandating that symptoms be emergent in later life, and using language targeted toward community dwelling functionally independent older adults (as opposed to dementia-centric language).…”

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).…”

Neuropsychiatric Symptoms and Mortality Among Patients With Mild Cognitive Impairment and Dementia Due to Alzheimer’s Disease

“…Elderly people with coexisting MBI and MCI have a higher risk of developing dementia than those with MCI alone [38] [39]. Furthermore, biomarker studies have suggested that patients with MBI share similar genetic pro les, brain betaamyloid imaging, and plasma neuro lament light with those with AD [40][41][42]. In addition to conversion to AD, our ndings highlight the clinical signi cance of NPS in MCI in terms of mortality and support the MBI concept, which allows for early identi cation and facilitates new possibilities for therapeutic intervention.…”