Episodic Memory and Hippocampal Volume Predict 5-Year Mild Cognitive Impairment Conversion in Healthy Apolipoprotein ε4 Carriers.

OBJECTIVE: The Apolipoprotein (APOE) ε4 allele increases the risk for mild cognitive impairment (MCI) and dementia, but not all carriers develop MCI/dementia. The purpose of this exploratory study was to determine if early and subtle preclinical signs of cognitive dysfunction and medial temporal lobe atrophy are observed in cognitively intact ε4 carriers who subsequently develop MCI. METHODS: Twenty-nine healthy, cognitively intact ε4 carriers (ε3/ε4 heterozygotes; ages 65-85) underwent neuropsychological testing and MRI-based measurements of medial temporal volumes over a 5-year follow-up interval; data were converted to z-scores based on a non-carrier group consisting of 17 ε3/ε3 homozygotes. RESULTS: At follow-up, 11 ε4 carriers (38%) converted to a diagnosis of MCI. At study entry, the MCI converters had significantly lower scores on the Mini-Mental State Examination, Rey Auditory Verbal Learning Test (RAVLT) Trials 1-5, and RAVLT Immediate Recall compared to non-converters. MCI converters also had smaller MRI volumes in the left subiculum than non-converters. Follow-up logistic regressions revealed that left subiculum volumes and RAVLT Trials 1-5 scores were significant predictors of MCI conversion. CONCLUSIONS: Results from this exploratory study suggest that ε4 carriers who convert to MCI exhibit subtle cognitive and volumetric differences years prior to diagnosis.

Anticholinergic/Sedative Drug Burden and Subjective Cognitive Decline in Older Adults at Risk of Alzheimer's Disease.

BACKGROUND: Anticholinergic/sedative drug use, measured by the Drug Burden Index (DBI), has been linked to cognitive impairment in older adults. Subjective cognitive decline (SCD) may be among the first symptoms patients with Alzheimer's disease (AD) experience. We examined whether DBI values are associated with SCD in older adults at risk of AD. We hypothesized that increased DBI would be associated with greater SCD at older ages. METHOD: Two-hundred-six community-dwelling, English-speaking adults (age = 65 ± 9 years) at risk of AD (42% apolipoprotein ε4 carriers; 78% with AD family history) were administered a single question to ascertain SCD: "Do you feel like your memory is becoming worse?" Response options were "No"; "Yes, but this does not worry me"; and "Yes, this worries me." DBI values were derived from self-reported medication regimens using older adult dosing recommendations. Adjusting for relevant covariates (comorbidities and polypharmacy), we examined independent effects of age and DBI on SCD, as well as the moderating effect of age on the DBI-SCD association at mean ± 1 SD of age. RESULTS: Both SCD and anticholinergic/sedative drug burden were prevalent. Greater drug burden was predictive of SCD severity, but age alone was not. A significant DBI*Age interaction emerged with greater drug burden corresponding to more severe SCD among individuals age 65 and older. CONCLUSION: Anticholinergic/sedative drug exposure was associated with greater SCD in adults 65 and older at risk for AD. Longitudinal research is needed to understand if this relationship is a pre-clinical marker of neurodegenerative disease and predictive of future cognitive decline.

Differential 5-year brain atrophy rates in cognitively declining and stable APOE-ε4 elders.

OBJECTIVE: The apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for late-onset Alzheimer's disease. Many ε4 carriers, however, never develop Alzheimer's disease. The purpose of this study is to characterize the variability in phenotypic expression of the ε4 allele, as measured by the longitudinal trajectory of cognitive test scores and MRI brain volumes, in cognitively intact elders. METHOD: Healthy older adults, ages 65-85, participated in a 5-year longitudinal study that included structural MRI and cognitive testing administered at baseline and at 1.5 and 5 years postenrollment. Participants included 22 ε4 noncarriers, 15 ε4 carriers who experienced a decline in cognition over the 5-year interval, and 11 ε4 carriers who remained cognitively stable. RESULTS: No baseline cognitive or volumetric group differences were observed. Compared to noncarriers, declining ε4 carriers had significantly greater rates of atrophy in left (p = .001, Cohen's d = .691) and right (p = .003, d = .622) cortical gray matter, left (p = .003, d = .625) and right (p = .020, d = .492) hippocampi, and greater expansion of the right inferior lateral ventricle (p < .001, d = .751) over 5 years. CONCLUSIONS: This study illustrates the variability in phenotypic expression of the ε4 allele related to neurodegeneration. Specifically, only those individuals who exhibited longitudinal declines in cognitive function experienced concomitant changes in brain volume. Future research is needed to better understand the biological and lifestyle factors that may influence the expression of the ε4 allele. (PsycINFO Database Record

Five-Year Longitudinal Brain Volume Change in Healthy Elders at Genetic Risk for Alzheimer's Disease.

Neuropathological changes associated with Alzheimer's disease (AD) precede symptom onset by more than a decade. Possession of an apolipoprotein E (APOE) ɛ4 allele is the strongest genetic risk factor for late onset AD. Cross-sectional studies of cognitively intact elders have noted smaller hippocampal/medial temporal volumes in ɛ4 carriers (ɛ4+) compared to ɛ4 non-carriers (ɛ4-). Few studies, however, have examined long-term, longitudinal, anatomical brain changes comparing healthy ɛ4+ and ɛ4- individuals. The current five-year study examined global and regional volumes of cortical and subcortical grey and white matter and ventricular size in 42 ɛ4+ and 30 ɛ4- individuals. Cognitively intact participants, ages 65-85 at study entry, underwent repeat anatomical MRI scans on three occasions: baseline, 1.5, and 4.75 years. Results indicated no between-group volumetric differences at baseline. Over the follow-up interval, the ɛ4+ group experienced a greater rate of volume loss in total grey matter, bilateral hippocampi, right hippocampal subfields, bilateral lingual gyri, bilateral parahippocampal gyri, and right lateral orbitofrontal cortex compared to the ɛ4- group. Greater loss in grey matter volumes in ɛ4+ participants were accompanied by greater increases in lateral, third, and fourth ventricular volumes. Rate of change in white matter volumes did not differentiate the groups. The current results indicate that longitudinal measurements of brain atrophy can serve as a sensitive biomarker for identifying neuropathological changes in persons at genetic risk for AD and potentially, for assessing the efficacy of treatments designed to slow or prevent disease progression during the preclinical stage of AD.