Bindu Patel

Elevated plasma amyloid β-peptide 1–42 and onset of dementia in adults with Down syndrome

We compared levels of plasma amyloid beta-peptides Abeta1-42 and Abeta1-40 in 108 demented and nondemented adults with Down syndrome (DS) and 64 adults from the general population. Abeta1-42 and Abeta1-40 levels were significantly higher in adults with DS than in controls (P=0.0001). Compared to nondemented adults with DS, Abeta1-42 levels in demented adults with DS were selectively increased by 26% (28.2 pg/ml vs. 22.4 pg/ml, P=0.004). In addition, mean plasma levels of Abeta1-42 were 22% higher in DS cases with the apolipoprotein varepsilon4 allele than in DS subjects without an varepsilon4 allele (25.9 pg/ml vs. 21.2 pg/ml, P=0.01), while mean plasma levels of Abeta1-40 did not vary by APOE genotype. These results support the hypothesis that Abeta1-42 plays an important role in the pathogenesis of dementia associated with DS, as it does in Alzheimers disease, and that variations in plasma levels may be related to disease progression.

Onset of dementia is associated with age at menopause in women with Down's syndrome.

Women with Downs syndrome experience early onset of both menopause and Alzheimers disease. This timing provides an opportunity to examine the influence of endogenous estrogen deficiency, indicated by age at menopause, on risk of Alzheimers disease. A community‐based sample of 163 postmenopausal women with Downs syndrome, 40 to 60 years of age, was ascertained through the New York State Developmental Disability service system. Information from cognitive assessments, medical record review, neurological evaluation, and caregiver interviews was used to establish ages for onset of menopause and dementia. We used survival and multivariate regression analyses to determine the relation of age at menopause to age at onset of Alzheimers disease, adjusting for age, level of mental retardation, body mass index, and history of hypothyroidism or depression. Women with early onset of menopause (46 years or younger) had earlier onset and increased risk of Alzheimers disease (AD) compared with women with onset of menopause after 46 years (rate ratio, 2.7; 95% confidence interval [CI], 1.2–5.9). Demented women had higher mean serum sex hormone binding globulin levels than nondemented women (86.4 vs 56.6 nmol/L, p = 0.02), but similar levels of total estradiol, suggesting that bioavailable estradiol, rather than total estradiol, is associated with dementia. Our findings support the hypothesis that reductions in estrogens after menopause contribute to the cascade of pathological processes leading to AD.

Body mass index, dementia, and mortality in the elderly

Objectives: To explore the association between body mass index and mortality in the elderly taking the diagnosis of dementia into account.Design: Cohort study.Setting: cohort study of aging in Medicare recipients in New York City.Participants: 1,452 elderly individuals 65 years and older of both genders.Measurements: We used proportional hazards regression for longitudinal multivariate analyses relating body mass index (BMI) and weight change to all-cause mortality.Results: There were 479 deaths during 9,974 person-years of follow-up. There were 210 cases of prevalent dementia at baseline, and 209 cases of incident dementia during follow-up. Among 1,372 persons with BMI information, the lowest quartile of BMI was associated with a higher mortality risk compared to the second quartile (HR = 1.5; 95% CI: 1.1,2.0) after adjustment for age, gender, education, ethnic group, smoking, cancer, and dementia. When persons with dementia were excluded, both the lowest (HR = 1.9; 95% CI =1.3,2.6) and highest (HR = 1.6; 95% CI: 1.1,2.3) quartiles of BMI were related to higher mortality. Weight loss was related to a higher mortality risk (HR = 1.5; 95% CI: 1.2,1.9) but this association was attenuated when persons with short follow-up or persons with dementia were excluded.Conclusion: The presence of dementia does not explain the association between low BMI and higher mortality in the elderly. However, dementia may explain the association between weight loss and higher mortality.

Obesity enhances verbal memory in postmenopausal women with Down syndrome

Several lines of evidence suggest that the loss of estrogen after menopause may play a role in cognitive declines associated with Alzheimers disease (AD). In postmenopausal women, the principal source of estrogen is estrone, which is influenced by body mass index (BMI). Increased BMI in postmenopausal women is associated with higher levels of serum estradiol and estrone. We hypothesized that obesity could have a beneficial effect on cognition with advancing age. We compared the performance of healthy nondemented obese and non-obese women with Down syndrome (DS) on a broad spectrum of cognitive tests. Estrone levels were 66.9% higher in obese than in non-obese postmenopausal women, and 136% higher in obese than in non-obese premenopausal women. Obese postmenopausal women performed significantly better than non-obese women on measures of verbal memory and on an omnibus test of neuropsychological function, but did not differ significantly in verbal fluency, language, praxis or visuospatial functioning. Among premenopausal women, there was no difference in cognitive function between obese and non-obese women. Our results support the hypothesis that higher endogenous estrogen levels after menopause are associated with better performance on verbal memory.

Effect of menopause on cognitive performance in women with Down syndrome.

We compared cognitive function in nondemented pre- and postmenopausal women with Down syndrome, aged 21–57 years, with their age-matched male peers. The Woodcock–Johnson Tests of Cognitive Ability–Revised were used to assess cognitive function at baseline and 2 years later. Premenopausal women performed better than their age-matched male peers, while postmenopausal women performed more poorly than age-matched male peers (p = 0.007). Premenopausal women and young men showed no significant declines in cognition over time. Postmenopausal women, but not their age-matched male peers, showed significant declines in cognitive function. Our results support the hypothesis that cognitive declines in postmenopausal women are associated with estrogen deficiency rather than with age.

Relation between vascular risk factors and neuropsychological test performance among elderly persons with Alzheimer's disease

BACKGROUND Vascular risk factors increase the risk of Alzheimers disease (AD). The mechanisms for these associations are unclear, and may be due to misdiagnosis of a vascular dementia syndrome as AD. OBJECTIVE To examine differences in neuropsychological profile among persons diagnosed clinically with AD with and without vascular risk factors or stroke. METHODS Community based cohort study. Individual and composite scores of neuropsychological tests at the time of clinical diagnosis of incident AD were compared among 243 persons with and without vascular risk factors or stroke. RESULTS Among subjects with incident AD, diabetes was associated with lower performance in Delayed Recall of the Selective Reminding Test (SRT), while persons diagnosed with hypertension scored lower in consistent long term recall (CLTR) of the SRT and current smokers scored lower in Category Fluency. None of the risk factors was associated with differences in composite scores in memory, abstract/visuospatial or language domain, nor was the number of risk factors per person. Persons with stroke had a higher delayed recall score at the time of AD diagnosis. CONCLUSION The presence of vascular risk factors among persons with clinically diagnosed AD was associated with subtle differences in neuropsychological profile at the time of diagnosis. This study needs to be replicated in samples with brain imaging, a comprehensive executive abilities battery, and pathological diagnosis of AD.

Measures of Adiposity and Dementia Risk in the Elderly

Community Health; #Geriatrics and Gerontology, University of Washington; zMental Illness Research and Education Clinical Center; **Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System; and w wCenter for Health Studies, Group Health Cooperative, Seattle, WA. Objective: To assess differential effect of statin therapy on risk of Alzheimer disease (AD) by age, sex, and presence of apolipoprotein E (APOE) e4 allele. Background: Although our previous study showed a null association between statins and risk of AD in subjects older than 65 years, statins may protective for AD in a subgroup of people who received statin therapy at relatively younger ages and carried the APOE-e4 allele. Methods: This is a prospective, cohort study of statin use and incident AD. A cohort of 2356, cognitively intact persons, aged 65 and older, were randomly selected from a large health maintenance organization, and were assessed biennially for dementia. Statin users were defined as those who received at least 3 prescriptions of a statin before onset of dementia by using the computerized pharmacy database. The potential effect modifiers included age-at-entry to study (65 to 79 vs Z80 y), sex, presence/absence of the APOE e4 allele, and preexisting of medical conditions. A proportional hazards model with statin use as a timedependent covariate was used to assess the statin-AD association. Results: Among 380 participants with incident dementia during four biennial follow-ups, 204 had probable AD. The hazard ratio for AD associated with statin use was 0.41 (95% CI 0.20-0.82) in the younger group and 1.96 (0.89 to 4.33) in the older group after adjusting for sex, education, baseline cognitive function, and other vascular risk factors. The interaction of age with statin was significant (P=0.05). Within the younger group, the adjusted hazard ratio with statin use was 0.19 (0.05 to 0.67) for males, and 0.73 (0.31 to 1.70) for females; 0.25 (0.09 to 0.73) in those with the APOE e4 allele, and was 0.72 (0.28 to 1.85) in those without the APOE e4 allele. The interaction of statin with either sex or APOE e4 did not reach statistical significance (P>0.05). Conclusion: Our findings are consistent with the idea that statin therapy is more likely to be protective for AD when given earlier (before age 80) and modifying effect of sex and APOE e4 allele needs to be further studied. Supported in part by grants AG20020, AG06781, AG16976, and AG05136 from the National Institute of Aging, National Institutes of Health. Disclosure: The authors report no conflicts of interest.