Association of Alzheimer's genetic loci with mild behavioral impairment

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.The study was supported by the National Health and Medical Research Council (NHMRC) grants 179805 and 1002160 and the NHMRC Dementia Collaborative Research Centre Early Diagnosis and Prevention. SJA is funded by the ARC Centre of Excellence in Population Ageing Research, ARC grant CE1101029. KJA is funded by NHMRC Research Fellowship No. 1002560. ZI is funded by the Hotchkiss Brain Institute with support from the Alzheimer Society Calgary. MEM is supported by the Australian National Health and Medical Research Council (NHMRC) and Australian Research Council (ARC) Dementia Research Development Fellowship #1102028