Parental History Of Alzheimer's Disease Research Articles

Reduced gray matter volume in normal adults with a maternal family history of Alzheimer disease

A consistently identified risk factor for Alzheimer disease (AD) is family history of dementia, with maternal transmission significantly more frequent than paternal transmission. A history of maternal AD may be related to AD-like glucose consumption in cognitively healthy subjects. In this cross-sectional study, we tested whether cognitively healthy people with a family history of AD have less gray matter volume (GMV), an endophenotype for late-onset AD, than individuals with no family history, and whether decreases in GMV are different in subjects with a maternal family history. As part of the Kansas University Brain Aging Project, 67 cognitively intact individuals with a maternal history of late-onset AD (FHm, n = 16), a paternal history of AD (FHp, n = 8), or no parental history of AD (FH-, n = 43), similar in age, gender, education, and Mini-Mental State Examination score, were scanned at 3 T. We used voxel-based morphometry to examine GMV differences between groups, controlling for age, gender, and apoE4. Cognitively healthy individuals with a family history of late-onset AD had significantly decreased GMV in the precuneus, middle frontal, inferior frontal, and superior frontal gyri compared with FH- individuals. FHm subjects had significantly smaller inferior frontal, middle frontal, precuneus, and lingual gyri compared with FH- and FHp subjects. Overall, maternal family history of Alzheimer disease (AD) in cognitively normal individuals is associated with lower gray matter volume in AD-vulnerable brain regions. These data complement and extend reports of cerebral metabolic differences in subjects with a maternal family history.

Vascular Factors and Markers of Inflammation in Offspring With a Parental History of Late-Onset Alzheimer Disease

Alzheimer disease (AD) is a complex disorder with a strong heritable component. Amyloid pathology, vascular factors, and inflammation are postulated to be involved in its pathogenesis, but causality has not been established unequivocally. To identify heritable traits in middle age that contribute to AD. We used a proven family design, comparing middle-aged offspring with and without a parental history of AD. In such a design, the offspring under study are enriched for risk factors of AD but do not yet have the disease. The Netherlands. Two hundred six offspring of 92 families with a parental history of late-onset AD and 200 offspring of 97 families without a parental history of AD. The APOE epsilon4 genotype, vascular factors, production capacity of pro- and anti-inflammatory cytokines upon stimulation with lipopolysaccharide, and circulating markers of inflammation. All outcome measures were assessed in the offspring only and not in the parental generation. More offspring with a parental history of AD carried APOE epsilon4 than those without a parental history of the disease (47% vs 21%, P < .001). Those with a parental history of AD also had higher systolic blood pressures (P = .006), higher diastolic blood pressures (P < .001), and lower ankle brachial indices (P = .005) when compared with offspring without a family history of dementia. Production capacity of pro-inflammatory cytokines in offspring with a parental history of AD was also different, with higher levels of IL-1beta (interleukin 1beta) (P < .001), IL-1beta to IL-1ra ratio (P < .001), tumor necrosis factor alpha (P = .008), IL-6 (P = .04), and interferon gamma (P = .01). All of these positive associations were independent of APOE epsilon4 genotype. Hypertension and the expression of an innate pro-inflammatory cytokine profile in middle age are early risk factors of AD in old age. For the offspring of affected families, it provides clues for screening and preventive strategies, of which blood pressure control can be implemented directly.

Parental history of Alzheimer disease associated with lower plasma apolipoprotein E levels

Variation in APOE genotype is a determinant of Alzheimer disease (AD), but the risk associated with variation in plasma apoE levels has yet to be determined. Here, we studied offspring with and without a parental history of AD to identify the effect of plasma apoE levels at middle age on the risk of late-onset AD. Some 203 offspring from 92 families with a parental history of AD were compared with 197 offspring from 97 families without a parental history of AD. APOE genotypes and plasma apoE levels were assessed in all offspring. Difference in plasma apoE level between subjects with and without a parental history of AD was calculated using robust linear regression, both stratified and adjusted for APOE genotype. Offspring with a parental history of AD were more likely to be an APOE epsilon4 allele carrier (46% vs 21%, p < 0.001) than offspring without such a parental history. Mean plasma apoE levels strongly decreased from epsilon2 to epsilon3epsilon3 to epsilon4 carriers (p < 0.001). Offspring with a parental history of AD had lower plasma apoE levels than subjects without such a history, both in analyses adjusted for APOE genotype (difference: -0.21 mg/dL, p = 0.02) and when using standardized Z scores, when stratified for APOE genotype (difference: -0.22, p = 0.009). Our findings suggest that lower plasma apoE levels in middle age could be a risk factor for Alzheimer disease in old age, independent of APOE genotype.

FMRI activation during episodic encoding and metacognitive appraisal across the lifespan: Risk factors for Alzheimer's disease

In the present study, we used fMRI to examine the influence of age on two other known risk factors for Alzheimer's disease (AD), APOE genotype and parental history of AD (FH status), during episodic encoding (ENC) and metacognitive self-appraisal (SA) paradigms. These paradigms have previously been shown to evoke activity from brain regions that are implicated in AD. First we examined the effect of age across the adult lifespan (age 18–84 years) on cerebral activity in a large sample ( n = 231) of cognitively healthy individuals. Next we examined a subset ( n = 155) on whom APOE status and FH status were known. For ENC, we found that increasing age was associated with reduced activity in the ventral temporal lobes and hippocampus. Our analysis of risk factors suggested that FH and age exerted independent effects, but APOE interacted with age such that APOE e4 carriers exhibit age-related increases in activity in the hippocampus. For the metacognitive SA task, increasing age was found to be associated with reduced activity in the medial prefrontal cortex, and increased activity in the mesial temporal lobe, posterior orbital cortex and striatum. Neither AD risk factor significantly modified age-related changes in brain activity during SA. These results suggest that FH and aging are exerting independent effects in both tasks while APOE affected the relationship with age in the hippocampus in one of the two tasks given.

PET sheds light on Alzheimer's disease genetic risk

Twenty-plus years of positron emission tomography (PET) data show that relative to cognitively intact controls, persons with Alzheimer's disease (AD) have reduced 2-[18F]fluoro-2-deoxy-d-glucose (FDG) uptake. This phenomenon is seen in brain regions containing amyloid plaques and neurofibrillary tangles, and supports the assertion that AD brains have reduced glucose consumption (1). From a diagnostic perspective, although the sensitivity of FDG PET in AD approaches that of the clinical impression, because its specificity is limited, PET is not used by itself to diagnose AD. Still, PET can refine the clinical impression, predict which patients with mild cognitive impairment (MCI) will progress to frank AD, and even help identify which normal elderly individuals are at greatest risk of cognitively declining within the next several years (1–3). In this issue of PNAS, Mosconi et al. (4) build upon and extend this line of work. They now report an analysis of PET scans from cognitively intact individuals with a maternal history of AD, a paternal history of AD, or no parental history of AD. PET findings were unremarkable in subjects without an affected parent and in subjects with an AD-affected father. PET scans from those with affected mothers, however, showed reduced parietal, temporal, medial temporal, frontal, and posterior cingulate glucose consumption. At face value, these data suggest that a maternally inherited genetic factor or factors influence brain metabolism.

IC-P-088: Reduced medial parietal activity in cognitively healthy middle-aged individuals with a parental history of Alzheimer’s disease

Medial parietal regions are vulnerable to some of the earliest structural and functional changes associated with Alzheimer's disease (AD). A growing body of research suggests that neuropathological changes occur in individuals at risk for AD, decades prior to symptom–onset. The current study employed functional MRI methods to examine function of medial parietal brain regions (i.e., posterior cingulate cortex and precuneus) in asymptomatic, middle–aged individuals who varied in their risk for AD. Prior fMRI research in healthy young adults indicates that medial parietal regions are active during both episodic retrieval and self–referential processing. Therefore, we administered an fMRI task that would allow examination of medial parietal function under both conditions. Participants included six at–risk individuals with a parental history of AD (mean age = 57.7 (1.8), mean education = 16.3 (2.1)) and six control participants with no parental history (mean age = 58.2 (3.1), mean education = 17.0 (3.0)). Participant groups were not significantly different with respect to age, education, or performance on visual and verbal memory tests. Whole–brain random–effects analysis of the groups' statistical parametric maps revealed that controls showed greater medial parietal activation than the at–risk group during both episodic retrieval and self–appraisal. This is depicted in Figures A and B (crosshairs depict activation described here). During episodic retrieval, the at–risk group showed significantly less activation than control individuals in the retrosplenial aspect of the posterior cingulate cortex (p = .01; see Figure A). During self–appraisal, at–risk individuals showed significantly less activation than controls in the precuneus (p > .001; see Figure B). The present study provides preliminary evidence for preclinical changes in medial parietal brain areas vulnerable to AD pathology. With continuing data collection, we will follow–up this work with an investigation of the influence of APOϵ4 and the interaction of family history and APOϵ4 on brain activity during both episodic retrieval and self–appraisal. Longitudinal follow–up of these participants will be needed to determine whether the findings we report are predictive of subsequent development of Mild Cognitive Impairment or AD.

Looking for signs of Alzheimer's disease.

This study examined the correlates of symptom-seeking behavior for Alzheimer's disease (AD) among middle-aged persons. Symptom seeking, the tendency to search for signs of disease, is one manifestation of an individual's concern about developing AD. The data were obtained from a survey of two subsamples of 40-60 year old adults: 1) 108 adult children with a living parent with a diagnosis of probable AD; and 2) 150 adults in a matched group with no parental history of AD. Bivariate and multivariate analyses were used to identify significant predictors of symptom seeking, which was measured by a composite index comprised of responses from three questions about checking for signs of AD, interpreting signs as symptoms of AD, and soliciting external validation for concerns. Four clusters of predictors were examined: memory assessment, AD experience, sociodemographics, and well-being. Within these clusters, the constellations of significant predictors varied by subsample, but the most robust predictors were aspects of subjective assessments of memory functioning and AD experience. An understanding of the correlates of symptom seeking for AD has implications for early detection of the disease as well as identifying populations under stress from excessive worry about their own future health.

To test or not to test: interest in genetic testing for Alzheimer's disease among middle-aged adults.

Based on a hypothetical scenario positing 100 percent accuracy in test results, we examined interest in genetic testing for Alzheimer's disease (AD) among adult children, 40-60 years of age, who have a living parent with a diagnosis of probable AD (N = 108), and a matched comparison group of persons with no parental history of AD (N = 150). For both groups, planning for the future was the most important reason cited for being tested; lack of good treatment options and concerns about losing health insurance were the most important reasons for not being tested. Hierarchical regression was used to examine the effects of sociodemographic characteristics, subjective perceptions of memory functioning, concerns about having and developing AD, and mastery on interest in being tested. Personal concerns about developing AD and mastery emerged as significant predictors and subsample membership approached significance, although the full model explained just 18 percent of the variance. Because persons in the comparison group were more likely to report an interest in being tested, educational efforts about genetic testing should not be restricted only to family members of persons with a diagnosis of AD.

Correlates of personal concerns about developing Alzheimer's disease among middle-aged persons.

We examine correlates of personal concerns about developing Alzheimer's disease (AD) among (1) adult children, 40 to 60 years of age, who have a living parent with a diagnosis of probable AD (N = 108), and (2) a matched comparison group of persons with no parental history of AD (N = 150). Using stepwise regression, predictors measuring subjective perceptions of memory functioning, overall family history of AD, knowledge of AD, and sociodemographic characteristics were entered into models for the total sample and each of the subsamples. The results indicate that worries about memory functioning play a consistent role in personal concerns about developing AD across both groups, but that additional pathways to personal concerns differ among individuals having and not having a parent with AD.