ApoE ε4 status in pre‐dementia risk states, mild behavioural impairment and subjective cognitive decline, and the risk of incident cognitive decline

Abstract

Background Dementia has an increasing global burden with over 40 million affected individuals. With sub‐optimal advances in drug development, there is an increasing shift to determine risk of dementia in the non‐demented population. Assessment of neuropsychiatric symptoms (NPS) may offer an opportunity to capture the at‐risk group earlier. Mild Behavioural Impairment (MBI) is a validated neurobehavioural syndrome, characterized by the emergence of sustained NPS in older adults as an at‐risk state for dementia. Cognitively, subjective cognitive decline (SCD) is a dementia at‐risk group in which cognitive symptoms are reported in the absence of objective findings. The apolipoprotein epsilon 4 (ApoE ε4) gene is a well‐known risk marker for dementia. We aim to determine the frequency of ApoE homozygosity in SCD, stratified by MBI status cross‐sectionally, and calculate the hazard of incident cognitive decline in this group longitudinally. Method Data from 5005 participants in the National Alzheimer’s Coordinating Center (NACC) were used to capture older adults who were cognitively normal, but had subjective cognitive complaints (SCD). We determined MBI status (+/‐) using a previously published transformation algorithm of NPI‐Q scores. We tabulated ApoE genotype in both groups. We compared proportion of ApoE homozygousity (APOE ε4+/+)in the MBI+ versus the MBI‐ group. Additionally, a Cox proportional hazards regression will be done to capture hazard of incident mild cognitive impairment in MBI+ versus MBI‐. Result A two‐sample test of proportions of MBI+/‐ status stratified by ApoE ε4+/+resulted in significant differences between groups with homozygosity more frequent in MBI+ versus MBI‐ (p<0.001). We will also present the results of the Cox proportional hazards regression analysis. Conclusion In older adults with subjective cognitive decline, ApoE ε4 allele homozygosity was more frequently seen in the MBI+ group. These findings provide additional evidence for the utility in determining MBI status in SCD.

Cognitive profile of people with mild behavioral impairment in Brain Health Registry participants

“…In a recent study of National Alzheimer Coordinating Center data, the combination of informantreported MBI and subjective cognitive decline (SCD) had a greater risk of incident cognitive and functional decline at 3 years compared to either MBI or SCD alone (Ismail et al, 2021). Further, in a subsequent study, those with SCD and MBI together had a shorter median time to incident MCI compared to those with SCD in the absence of MBI (Nathan et al, 2020). Taken together the results suggest that individuals with subtle neuropsychological test score differences and MBI together may be at higher risk for cognitive and functional decline.…”

Psychosis in Alzheimer disease — mechanisms, genetics and therapeutic opportunities

“…Consistent with the previous literature 169 , cases are over-represented in clinical versus community samples. Longitudinal cohorts have demonstrated associations between MBI and cognitive decline, incident MCI, and incident dementia 160,162,167,170,171 and MBI has also been linked to known dementia markers, including Aβ 172,173 , tau 174,175 , white matter atrophy 176 , grey matter atrophy 177 , plasma neurofilament light 178 and AD risk loci 179,180 .…”

Cognitive profile of mild behavioral impairment in Brain Health Registry participants

“…In a recent study of National Alzheimer Coordinating Center data, the combination of informant-reported MBI and subjective cognitive decline (SCD) had a greater risk of incident cognitive and functional decline at three years compared to either MBI or SCD alone 24 . Further, in a subsequent study, those with SCD and MBI together had a shorter median time to incident MCI compared to those with SCD in the absence of MBI 48 . Taken together the results suggest that individuals with subtle neuropsychological test score differences and MBI together may be at higher risk for cognitive and functional decline.…”