Asenath La Rue

Middle-aged children of persons with Alzheimer's disease: APOE genotypes and cognitive function in the Wisconsin Registry for Alzheimer's Prevention.

Adult children of persons with Alzheimer’s disease are at increased risk of developing Alzheimer’s disease because of hereditary, environmental, and health risk factors shared with affected parents. The Wisconsin Registry for Alzheimer’s Prevention (WRAP) has completed baseline assessments on 452 middle-aged persons (mean = 53 years) who have at least 1 parent with AD. Forty-five percent had 1 or more apolipoprotein (APOE) ε4 alleles. There were few significant differences between ε4 carriers and noncarriers in demographics, health, and lifestyle measures or in neuropsychological performance. The high percentage of WRAP participants who are carriers of APOE ε4 underscores their increased risk for developing Alzheimer’s disease, but the absence of differences related to APOE status and high mean scores on cognitive tests suggests that the APOE ε4 gene has yet to have a clinical impact on cognitive functioning. The WRAP cohort may be a valuable group to follow prospectively to characterize the nature of cognitive change in relation to risk factors and to identify underlying preclinical neurobiological changes.

Criteria for diagnosing age-associated memory impairment: proposed improvements from the field

We pooled clinical and research experience to suggest revised criteria for diagnosing age‐associated memory impairment and to propose guidelines for identifying more select subgroups with age‐consistent memory impairment and late‐life forgetfulness.

Association of Insulin Resistance With Cerebral Glucose Uptake in Late Middle–Aged Adults at Risk for Alzheimer Disease

IMPORTANCE Converging evidence suggests that Alzheimer disease (AD) involves insulin signaling impairment. Patients with AD and individuals at risk for AD show reduced glucose metabolism, as indexed by fludeoxyglucose F 18-labeled positron emission tomography (FDG-PET). OBJECTIVES To determine whether insulin resistance predicts AD-like global and regional glucose metabolism deficits in late middle-aged participants at risk for AD and to examine whether insulin resistance-predicted variation in regional glucose metabolism is associated with worse cognitive performance. DESIGN, SETTING, AND PARTICIPANTS This population-based, cross-sectional study included 150 cognitively normal, late middle-aged (mean [SD] age, 60.7 [5.8] years) adults from the Wisconsin Registry for Alzheimers Prevention (WRAP) study, a general community sample enriched for AD parental history. Participants underwent cognitive testing, fasting blood draw, and FDG-PET at baseline. We used the homeostatic model assessment of peripheral insulin resistance (HOMA-IR). Regression analysis tested the statistical effect of HOMA-IR on global glucose metabolism. We used a voxelwise analysis to determine whether HOMA-IR predicted regional glucose metabolism. Finally, predicted variation in regional glucose metabolism was regressed against cognitive factors. Covariates included age, sex, body mass index, apolipoprotein E ε4 genotype, AD parental history status, and a reference region used to normalize regional uptake. MAIN OUTCOMES AND MEASURES Regional glucose uptake determined using FDG-PET and neuropsychological factors. RESULTS Higher HOMA-IR was associated with lower global glucose metabolism (β = -0.29; P < .01) and lower regional glucose metabolism across large portions of the frontal, lateral parietal, lateral temporal, and medial temporal lobes (P < .05, familywise error corrected). The association was especially robust in the left medial temporal lobe (R2 = 0.178). Lower glucose metabolism in the left medial temporal lobe predicted by HOMA-IR was significantly related to worse performance on the immediate memory (β = 0.317; t148 = 4.08; P < .001) and delayed memory (β = 0.305; t148 = 3.895; P < .001) factor scores. CONCLUSIONS AND RELEVANCE Our results show that insulin resistance, a prevalent and increasingly common condition in developed countries, is associated with significantly lower regional cerebral glucose metabolism, which in turn may predict worse memory performance. Midlife may be a critical period for initiating treatments to lower peripheral insulin resistance to maintain neural metabolism and cognitive function.

Recombinant Human Erythropoietin Treatment May Improve Quality of Life and Cognitive Function in Chronic Hemodialysis Patients

Medical, psychological, and social adaptation (quality of life) as well as cognitive function were studied in 15 chronic stable hemodialysis patients before the onset of treatment with recombinant human erythropoietin (r-HuEPO), 1 month after stabilization of normal hematocrit levels, and 10 to 15 months after treatment onset. After r-HuEPO treatment, subjects had significantly higher hematocrits, markedly improved energy levels, and marginally improved global health. r-HuEPO treatment was also associated with progressively decreased levels of subject mood disturbance and dialysis-related stresses. Subjects had no increased participation in paid employment and only minimally increased participation in social and leisure activities at posttreatment data points. There was no significant improvement in cognitive function after treatment. r-HuEPO treatment appears to be associated with higher energy levels, significant psychological benefits, and minimal improvements in social adaptation. The effects on cognitive function merit further study.

Insulin Resistance, Brain Atrophy, and Cognitive Performance in Late Middle–Aged Adults

OBJECTIVE Insulin resistance dysregulates glucose uptake and other functions in brain areas affected by Alzheimer disease. Insulin resistance may play a role in Alzheimer disease etiopathogenesis. This longitudinal study examined whether insulin resistance among late middle–aged, cognitively healthy individuals was associated with 1) less gray matter in Alzheimer disease–sensitive brain regions and 2) worse cognitive performance. RESEARCH DESIGN AND METHODS Homeostasis model assessment of insulin resistance, gray matter volume, and the Rey Auditory Verbal Learning Test (RAVLT) were acquired in 372 participants at baseline and a consecutive subset of 121 individuals ~4 years later. Voxel-based morphometry and tensor-based morphometry were used, respectively, to test the association of insulin resistance with baseline brain volume and progressive gray matter atrophy. RESULTS Higher insulin resistance predicted less gray matter at baseline and 4 years later in medial temporal lobe, prefrontal cortices, precuneus, and other parietal gyri. A region-of-interest analysis, independent of the voxel-wise analyses, confirmed that higher insulin resistance was related to medial temporal lobe atrophy. Atrophy itself corresponded to cognitive deficits in the RAVLT. Temporal lobe atrophy that was predicted by higher insulin resistance significantly mediated worse RAVLT encoding performance. CONCLUSIONS These results suggest that insulin resistance in an asymptomatic, late middle–aged cohort is associated with progressive atrophy in regions affected by early Alzheimer disease. Insulin resistance may also affect the ability to encode episodic information by negatively influencing gray matter volume in medial temporal lobe.

Cognitive function and prediction of dementia in old age.

Longitudinal changes in cognitive functioning were examined for a sample of aging twins, some of whom developed dementia while others did not. Individuals who were judged to be demented at a mean age of eighty-five years had achieved lower scores on most tests twenty years prior to diagnosis, and experienced greater declines in vocabulary and forward digit span over time, than those surviving to a comparable age without dementia. These trends were observed for individuals with mild, as well as moderate-to-severe, dementia and were unrelated to physical health status or premorbid activity patterns. It is suggested that dementing illness may develop very slowly, and that the likelihood of exhibiting clinically significant dementia may vary with premorbid intellectual level.

Insulin resistance predicts brain amyloid deposition in late middle-aged adults

Insulin resistance (IR) increases Alzheimers disease (AD) risk. IR is related to greater amyloid burden post‐mortem and increased deposition within areas affected by early AD. No studies have examined if IR is associated with an in vivo index of amyloid in the human brain in late middle‐aged participants at risk for AD.

The effect of TOMM40 poly-T length on gray matter volume and cognition in middle-aged persons with APOE ɛ3/ɛ3 genotype

Apolipoprotein E (APOE) genotypes are associated with variable risk of developing late‐onset Alzheimers disease (LOAD), with APOE epsilon 4 (APOE ɛ4) having higher risk. A variable poly‐T length polymorphism at rs10524523, within intron 6 of the translocase of the outer mitochondrial membrane (TOMM40) gene, has been shown to influence age of onset in LOAD, with very long (VL) poly‐T length associated with earlier disease onset, and short poly‐T length associated with later onset. In this study, we tested the hypothesis that brain and cognitive changes suggestive of presymptomatic LOAD may be associated with this TOMM40 polymorphism.

Effect of parental family history of Alzheimer's disease on serial position profiles

An exaggerated recency effect (ie, disproportionate recall of last‐presented items) has been consistently observed in the word list learning of patients with Alzheimers disease (AD). Our study sought to determine whether there were similar alterations in serial position learning among asymptomatic persons at risk for AD as a result of parental family history.

Latent Structure and Factorial Invariance of a Neuropsychological Test Battery for the Study of Preclinical Alzheimer's Disease

OBJECTIVE To examine the latent structure of a test battery currently being used in a longitudinal study of asymptomatic middle-aged adults with a parental history of Alzheimers disease (AD) and test the invariance of the factor solution across subgroups defined by selected demographic variables and known genetic risk factors for AD. METHOD An exploratory factor analysis (EFA) and a sequence of confirmatory factor analyses (CFA) were conducted on 24 neuropsychological measures selected to provide a comprehensive estimate of cognitive abilities most likely to be affected in preclinical AD. Once the underlying latent model was defined and the structural validity established through model comparisons, a multigroup confirmatory factor analysis model was used to test for factorial invariance across groups. RESULTS The EFA solution revealed a factor structure consisting of five constructs: verbal ability, visuospatial ability, speed & executive function, working memory, and verbal learning & memory. The CFA models provided support for the hypothesized 5-factor structure. Results indicated factorial invariance of the model across all groups examined. CONCLUSIONS Collectively, the results suggested a relatively strong psychometric basis for using the factor structure in clinical samples that match the characteristics of this cohort. This confirmed an invariant factor structure should prove useful in research aimed to detect the earliest cognitive signature of preclinical AD in similar middle aged cohorts.