Nicole Schupf

Physical Activity, Diet, and Risk of Alzheimer Disease

CONTEXT Both higher adherence to a Mediterranean-type diet and more physical activity have been independently associated with lower Alzheimer disease (AD) risk but their combined association has not been investigated. OBJECTIVE To investigate the combined association of diet and physical activity with AD risk. DESIGN, SETTING, AND PATIENTS Prospective cohort study of 2 cohorts comprising 1880 community-dwelling elders without dementia living in New York, New York, with both diet and physical activity information available. Standardized neurological and neuropsychological measures were administered approximately every 1.5 years from 1992 through 2006. Adherence to a Mediterranean-type diet (scale of 0-9; trichotomized into low, middle, or high; and dichotomized into low or high) and physical activity (sum of weekly participation in various physical activities, weighted by the type of physical activity [light, moderate, vigorous]; trichotomized into no physical activity, some, or much; and dichotomized into low or high), separately and combined, were the main predictors in Cox models. Models were adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, body mass index, smoking status, depression, leisure activities, a comorbidity index, and baseline Clinical Dementia Rating score. MAIN OUTCOME MEASURE Time to incident AD. RESULTS A total of 282 incident AD cases occurred during a mean (SD) of 5.4 (3.3) years of follow-up. When considered simultaneously, both Mediterranean-type diet adherence (compared with low diet score, hazard ratio [HR] for middle diet score was 0.98 [95% confidence interval {CI}, 0.72-1.33]; the HR for high diet score was 0.60 [95% CI, 0.42-0.87]; P = .008 for trend) and physical activity (compared with no physical activity, the HR for some physical activity was 0.75 [95% CI, 0.54-1.04]; the HR for much physical activity was 0.67 [95% CI, 0.47-0.95]; P = .03 for trend) were associated with lower AD risk. Compared with individuals neither adhering to the diet nor participating in physical activity (low diet score and no physical activity; absolute AD risk of 19%), those both adhering to the diet and participating in physical activity (high diet score and high physical activity) had a lower risk of AD (absolute risk, 12%; HR, 0.65 [95% CI, 0.44-0.96]; P = .03 for trend). CONCLUSION In this study, both higher Mediterranean-type diet adherence and higher physical activity were independently associated with reduced risk for AD.

Mediterranean Diet and Mild Cognitive Impairment

BACKGROUND Higher adherence to the Mediterranean diet (MeDi) may protect from Alzheimer disease (AD), but its association with mild cognitive impairment (MCI) has not been explored. OBJECTIVE To investigate the association between the MeDi and MCI. DESIGN, SETTING, AND PATIENTS In a multiethnic community study in New York, we used Cox proportional hazards to investigate the association between adherence to the MeDi (0-9 scale; higher scores indicate higher adherence) and (1) the incidence of MCI and (2) the progression from MCI to AD. All of the models were adjusted for cohort, age, sex, ethnicity, education, APOE genotype, caloric intake, body mass index, and duration between baseline dietary assessment and baseline diagnosis. MAIN OUTCOME MEASURES Incidence of MCI and progression from MCI to AD. RESULTS There were 1393 cognitively normal participants, 275 of whom developed MCI during a mean (SD) follow-up of 4.5 (2.7) years (range, 0.9-16.4 years). Compared with subjects in the lowest MeDi adherence tertile, subjects in the middle tertile had 17% less risk (hazard ratio [HR] = 0.83; 95% confidence interval [CI], 0.62-1.12; P = .24) of developing MCI and those in the highest tertile had 28% less risk (HR = 0.72; 95% CI, 0.52-1.00; P = .05) of developing MCI (trend HR = 0.85; 95% CI, 0.72-1.00; P for trend = .05). There were 482 subjects with MCI, 106 of whom developed AD during a mean (SD) follow-up of 4.3 (2.7) years (range, 1.0-13.8 years). Compared with subjects in the lowest MeDi adherence tertile, subjects in the middle tertile had 45% less risk (HR = 0.55; 95% CI, 0.34-0.90; P = .01) of developing AD and those in the highest tertile had 48% less risk (HR = 0.52; 95% CI, 0.30-0.91; P = .02) of developing AD (trend HR = 0.71; 95% CI, 0.53-0.95; P for trend = .02). CONCLUSIONS Higher adherence to the MeDi is associated with a trend for reduced risk of developing MCI and with reduced risk of MCI conversion to AD.

Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation

Allele-specific DNA methylation (ASM) is a hallmark of imprinted genes, but ASM in the larger nonimprinted fraction of the genome is less well characterized. Using methylation-sensitive SNP analysis (MSNP), we surveyed the human genome at 50K and 250K resolution, identifying ASM as recurrent genotype call conversions from heterozygosity to homozygosity when genomic DNAs were predigested with the methylation-sensitive restriction enzyme HpaII. Using independent assays, we confirmed ASM at 16 SNP-tagged loci distributed across various chromosomes. At 12 of these loci (75%), the ASM tracked strongly with the sequence of adjacent SNPs. Further analysis showed allele-specific mRNA expression at two loci from this methylation-based screen—the vanin and CYP2A6-CYP2A7 gene clusters—both implicated in traits of medical importance. This recurrent phenomenon of sequence-dependent ASM has practical implications for mapping and interpreting associations of noncoding SNPs and haplotypes with human phenotypes.

Plasma Aβ40 and Aβ42 and Alzheimer's Disease: Relation to Age, Mortality, and Risk

BackgroundPlasma amyloid &bgr;-peptide (A&bgr;) 40 and A&bgr;42 levels are increased in persons with mutations causing early-onset familial Alzheimer’s disease (AD). Plasma A&bgr;42 levels were also used to link microsatellite genetic markers to a putative AD genetic locus on chromosome 10 and were observed in patients with incipient sporadic AD. MethodsThe authors measured plasma A&bgr;40 and A&bgr;42 levels using a sandwich ELISA after the initial examination of 530 individuals participating in an epidemiologic study of aging and dementia. Participants were examined at 18-month intervals, and plasma A&bgr;40 and A&bgr;42 levels were repeated in 307 subjects 3 years after baseline. ResultsCompared with individuals who never developed AD, patients with AD at baseline and those who developed AD during the follow-up had significantly higher A&bgr;42, but not A&bgr;40, plasma levels. The risk of AD in the highest quartile of plasma A&bgr;42 was increased by more than twofold over that in the lowest quartile. The highest plasma A&bgr;42 levels were observed in patients with AD who died during the follow-up. Plasma A&bgr;42, but not A&bgr;40, levels decreased over time in patients with newly acquired AD. ConclusionsPlasma A&bgr;40 and A&bgr;42 increase with age and are strongly correlated with each other. Plasma A&bgr;40 and A&bgr;42 levels are elevated in some patients before and during the early stages of AD but decline thereafter. High plasma A&bgr;42 levels may also be associated with mortality in patients with AD.

Frequency and Course of Mild Cognitive Impairment in a Multiethnic Community

To examine incidence rates and antecedents of mild cognitive impairment (MCI) and Alzheimers disease (AD) among diverse elders without dementia at the initial visit, and to examine the characteristics of elders with MCI who reverted to normal on follow‐up examination.

Peripheral Aβ subspecies as risk biomarkers of Alzheimer's disease

Plasma Aβ42 and Aβ40 levels are putative biomarkers for Alzheimers disease (AD), but their significance and predictive value have been inconclusive. In AD transgenic models, plasma and cerebrospinal fluid levels of Aβ42 and Aβ40 increase with age but subsequently decrease when Aβ begins to accumulate in brain and with the onset of cognitive impairment. To determine the predictive value of Aβ levels in elderly populations, we investigated how plasma Aβ42, Aβ40, and a protofibrillar subspecies of Aβ42 changed over time and with the onset of cognitive impairment or AD. In a cohort of 1,125 elderly persons without dementia, 104 (9.2%) of the participants developed AD over 4.6 years of follow-up. Higher plasma Aβ42 levels at the onset of the study were associated with a threefold increased risk of AD. However, conversion to AD was accompanied by a significant decline in plasma Aβ42, a decreased Aβ42/Aβ40 ratio and, with the onset of cognitive impairment, decreased protofibrillar Aβ42 levels. Our results suggest individuals with elevated plasma Aβ42 are at increased risk of AD and that with the onset of disease, the decline in some forms of Aβ may reflect compartmentalization of Aβ peptides in the brain.

Cognitive Decline and Literacy Among Ethnically Diverse Elders

Researchers on genetic and environmental influences on risk for Alzheimer’s disease must be prepared for the growing ethnic and racial diversity of our participants. Within the investigation, years of education has typically served as a proxy for cognitive reserve, which may be one factor in influencing risk of cognitive decline among aging people. However, among ethnic minorities, years of education is a poor reflection of the value of educational experience and native ability. This study was conducted among 1002 ethnically diverse English-speaking residents of Northern Manhattan who were cognitively and functionally normal at a baseline evaluation. We found that literacy level was a better predictor of decline in memory, executive function, and language skills than was years of education. The results of this study suggest that in an ethnically diverse cohort, literacy level should be considered as a mediator of the interactions of biological and environmental factors on cognitive decline.

Combined Effect of Age and Severity on the Risk of Dementia in Parkinson's Disease

Age and severity of extrapyramidal signs have been consistently associated with incident dementia in Parkinsons disease. We evaluated the separate and combined effects of age and severity of extrapyramidal signs on the risk of incident dementia in Parkinsons disease in the setting of a population‐based prospective cohort study. Age and the total Unified Parkinsons Disease Rating Scale motor score at baseline evaluation were dichotomized at the median. Four groups of Parkinsons disease patients were defined: younger age/low severity (reference), younger age/high severity, older age/low severity, and older age/high severity. Risk ratios for incident dementia were calculated with Cox proportional hazards models controlling for gender, education, ethnicity, and duration of Parkinsons disease. Of 180 patients, 52 (28.9%) became demented during a mean follow‐up period of 3.6 ± 2.2 years. The median age at baseline of the Parkinsons disease patients was 71.8 years (range, 38.5–95.9 years), and the median total Unified Parkinsons Disease Rating Scale motor score was 24 (range, 2–65). The group with older age/high severity had a significantly increased risk of incident dementia (relative risk, 9.7; 95% confidence interval, 3.9–24.4) compared with the group with younger age/low severity (reference), whereas the groups with older age/low severity (relative risk, 1.6; 95% confidence interval, 0.5–4.8) and younger age/high severity (relative risk, 1.2; 95% confidence interval, 0.5–3.2) did not. These findings suggest that the increased risk of incident dementia in Parkinsons disease associated with age and severity of extrapyramidal signs is related primarily to their combined effect rather than separate effects.

Prevalence of Chronic Medical Conditions in Adults with Mental Retardation: Comparison with the General Population.

We interviewed caregivers and reviewed medical records of 278 adults with mental retardation with and without Down syndrome, 45 to 74 years of age. Standardized morbidity ratios were used to compare frequency of medical disorders in these adults to frequency in the general population. In adults with mental retardation, the frequency of common age-related disorders was comparable to that in the general population, but there was an increased frequency of thyroid disorders, nonischemic heart disorders, and sensory impairment. Surveillance of health status and increased access to health care for screening and treatment of age-related disorders that are more frequent in adults with mental retardation would be important to prevent the development or delay the impact of these conditions and to promote healthy aging.

Shorter telomeres are associated with mortality in those with APOE ϵ4 and dementia

Reduced telomere length may be a marker of biological aging. We hypothesized that telomere length might thus relate to increased risk for dementia and mortality.