Effects of Vascular Risk Factors on the Association of Blood-Based Biomarkers with Alzheimer's Disease.

Background: Comorbidities may influence the levels of blood-based biomarkers for Alzheimer's disease (AD). We investigated whether differences in risk factors or comorbid conditions might explain the discordance between clinical diagnosis and biomarker classifications in a multi-ethnic cohort of elderly individuals. Aims: To evaluate the relationship of medical conditions and other characteristics, including body mass index (BMI), vascular risk factors, and head injury, with cognitive impairment and blood-based biomarkers of AD, phosphorylated tau (P-tau 181, P-tau 217), in a multi-ethnic cohort. Methods: Three-hundred individuals, aged 65 and older, were selected from a prospective community-based cohort for equal representation among three racial/ethnic groups: non-Hispanic White, Hispanic/Latino and African American/Black. Participants were classified into four groups based on absence (Asym) or presence (Sym) of cognitive impairment and low (NEG) or high (POS) P-tau 217 or P-tau 181 levels, determined previously in the same cohort: (Asym/NEG, Asym/POS, Sym/NEG, Sym/POS). We examined differences in individual characteristics across the four groups. We performed post-hoc analysis examining the differences across biomarker and cognitive status. Results: P-tau 217 or P-tau 181 positive individuals had lower BMI than P-tau negative participants, regardless of symptom status. Symptomatic and asymptomatic participants did not differ in terms of BMI. BMI was not a mediator of the effect of P-tau 217 or P-tau 181 on dementia. Frequencies of other risk factors did not differ between the four groups of individuals. Conclusions: Participants with higher levels of P-tau 217 or P-tau 181 consistent with AD had lower BMI regardless of whether the individual was symptomatic. These findings suggest that weight loss may change with AD biomarker levels before onset of cognitive decline. They do not support BMI as a confounding variable. Further longitudinal studies could explore the relationship of risk factors with clinical diagnoses and biomarkers.

Dietary fatty acids and risk of Alzheimer's disease and related dementias: Observations from the Washington Heights-Hamilton Heights-Inwood Columbia Aging Project (WHICAP).

INTRODUCTION: High dietary intake of long chain, polyunsaturated fatty acids is associated with lower Alzheimer's disease (AD) risk. METHODS: Washington Heights-Hamilton Heights-Inwood Columbia Aging Project is a multiethnic, prospective observational study of aging and dementia among elderly (≥ 65 years). Dietary intake was measured using a food frequency questionnaire. Dietary short-, medium-, and long-chain fatty acid intakes were categorized by number of carbons and double bonds. Consensus AD diagnoses were made. Associations between AD risk and dietary fatty acid and cholesterol intakes were estimated using multivariable Cox proportional hazards regression models. RESULTS: Of 2612 multiethnic women (67%) and men (baseline age 76.3 [6.4] years), 380 developed AD over an average 4.5 years follow-up. Lower risk of AD was associated with increasing intakes of docosahexaenoic acid (DHA; hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.57 to 0.95, P = 0.018) and eicosapentaenoic acid (EPA; HR = 0.74, 95% CI: 0.57 to 0.95, P = 0.021), and longer AD-free survival (P < 0.05). DISCUSSION: Higher intake of DHA and EPA are protective for AD.

Anxiety symptoms bias memory assessment in older adults.

BACKGROUND: Older adults with anxiety and/or depression experience additional memory dysfunction beyond that of the normal aging process. However, few studies have examined test bias in memory assessments due to anxiety and/or depressive symptoms. The current study investigated the influence of self-reported symptoms of anxiety and depression on the measurement equivalence of memory tests in older adults. METHOD: This is a secondary analysis of the Advanced Cognitive Training for Independent and Vital Elderly dataset, a randomized controlled trial of community-dwelling older adults. Baseline data were included in this study (n = 2802). Multiple indicators multiple causes modeling was employed to assess for measurement equivalence, differential item functioning (DIF), in memory tests. RESULTS: The DIF was present for anxiety symptoms but not for depressive symptoms, such that higher anxiety placed older adults at a disadvantage on measures of memory performance. Analysis of DIF impact showed that compared with participants scoring in the bottom quartile of anxious symptoms, participants in the upper quartile exhibited memory performance scores that were 0.26 standard deviation lower. CONCLUSION: Anxious but not depressive symptoms introduce test bias into the measurement of memory in older adults. This indicates that memory models for research and clinical purposes should account for the direct relationship between anxiety symptoms and memory tests in addition to the true relationship between anxiety symptoms and memory construct. These findings support routine assessments of anxiety symptoms among older adults in settings in which cognitive testing is being conducted. Copyright © 2016 John Wiley & Sons, Ltd.

Memory after silent stroke: hippocampus and infarcts both matter.

OBJECTIVE: Memory decline commonly occurs among elderly individuals. This observation is often attributed to early neurodegenerative changes in the hippocampus and related brain regions. However, the contribution of vascular lesions, such as brain infarcts, to hippocampal integrity and age-associated memory decline remains unclear. METHODS: We studied 658 elderly participants without dementia from a prospective, community-based study on aging and dementia who received high-resolution structural MRI. Cortical and subcortical infarcts were identified, and hippocampal and relative brain volumes were calculated following standard protocols. Summary scores reflecting performance on tasks of memory, language, processing speed, and visuospatial function were derived from a comprehensive neuropsychological battery. We used multiple regression analyses to relate cortical and subcortical infarcts, hippocampal and relative brain volume, to measures of cognitive performance in domains of memory, language, processing speed, and visuospatial ability. RESULTS: Presence of brain infarcts was associated with a smaller hippocampus. Smaller hippocampus volume was associated with poorer memory specifically. Brain infarcts were associated with poorer memory and cognitive performance in all other domains, which was independent of hippocampus volume. CONCLUSIONS: Both hippocampal volume and brain infarcts independently contribute to memory performance in elderly individuals without dementia. Given that age-associated neurodegenerative conditions, such as Alzheimer disease, are defined primarily by impairment in memory, these findings have clinical implications for prevention and for identification of pathogenic factors associated with disease symptomatology.

Subclinical cerebrovascular disease in mild cognitive impairment.

BACKGROUND: Cerebrovascular disease (CVD) may contribute to mild cognitive impairment (MCI). We sought to determine the relation of white matter hyperintensity (WMH) volume and infarcts in brain MRI to MCI in a community-based sample. METHODS: A total of 679 elderly persons without dementia underwent brain MRI. WMH and infarcts were quantified using research methods. WMH was adjusted for total cranial volume. The Petersen criteria were used to define MCI. MCI was further subclassified into amnestic and non-amnestic. We used logistic regression to relate WMH and infarcts to prevalent MCI. RESULTS: WMH were associated with amnestic MCI (odds ratio [OR] = 1.9; 95% confidence interval [CI] 1.1, 3.4) but not non-amnestic MCI (OR = 1.2; 95% CI 0.4, 1.6) after adjusting for age, gender, ethnic group, education, and APOE-epsilon4. Infarcts were more strongly associated with non-amnestic MCI (OR = 2.7; 95% CI 1.5, 4.8) than amnestic MCI (OR = 1.4; 95% CI 0.9, 2.3). In secondary analyses using continuous cognitive scores as outcomes, WMH, but not infarcts, were related to memory, while infarcts were more strongly related with non-amnestic domains. CONCLUSION: White matter hyperintensity (WMH) is more strongly related to amnestic mild cognitive impairment (MCI). Infarcts are more strongly related to non-amnestic MCI. The nature of WMH in amnestic MCI requires further study.

Education and rates of cognitive decline in incident Alzheimer's disease.

BACKGROUND: Some (but not all) epidemiological studies have noted faster rates of progression in high education patients with Alzheimer's disease (AD), which has been attributed to harbouring/tolerating a higher pathological burden at the time of clinical dementia for subjects with higher education. We wanted to assess the relationship between education and rates of decline in AD. METHODS: During the course of a community based multiethnic prospective cohort study of individuals aged > or = 65 years living in New York, 312 patients were diagnosed with incident AD and were followed overall for 5.6 (up to 13.3) years. The subjects received an average of 3.7 (up to 9) neuropsychological assessments consisting of 12 individual tests. With the aid of a normative sample, a standardised composite cognitive score as well as individual cognitive domain scores were calculated. Generalised estimating equation models were used to examine the association between education and rates of cognitive decline. RESULTS: Composite cognitive performance declined by 9% of a standard deviation per year. Rates of decline before and after AD incidence were similar. For each additional year of education there was 0.3% standard deviation lower composite cognitive performance for each year of follow up. The association between higher education and faster decline was noted primarily in the executive speed (0.6%) and memory (0.5%) cognitive domains and was present over and above age, gender, ethnicity, differential baseline cognitive performance, depression, and vascular comorbidity. CONCLUSIONS: We conclude that higher education AD patients experience faster cognitive decline.

Association between mild parkinsonian signs and mild cognitive impairment in a community.

BACKGROUND: Mild parkinsonian signs (MPS) are associated with prevalent and incident dementia but it is not known whether they are associated with mild cognitive impairment (MCI). OBJECTIVE: To determine whether MPS and specific MPS (changes in axial function, rigidity, tremor) are associated with MCI in nondemented community-dwelling older people in northern Manhattan, NY. METHODS: Participants underwent neurologic assessment, including a modified motor portion of the Unified Parkinson Disease Rating Scale. MCI was diagnosed in nondemented participants who had cognitive impairment based on neuropsychological testing and no functional impairment. Participants with MCI were classified as having MCI with memory impairment (MCI+M) vs MCI without memory impairment (MCI-M). RESULTS: MCI was present in 608 (27.3%) of 2,230 participants, including 255 participants with MCI+M and 353 with MCI-M; 1,622 participants did not have MCI. MPS were present in 369 (16.5%) of 2,230 participants. In a univariate logistic regression model, odds of MCI+M (vs no MCI) were 51% higher in participants with MPS compared to those with no MPS (OR = 1.51, 95% CI = 1.09 to 2.09, p = 0.01). Multivariate models yielded similar results (OR = 1.45, 95% CI = 1.03 to 2.05, p = 0.03). Rigidity was present in a higher proportion of participants with MCI+M compared to participants without MCI. CONCLUSIONS: Mild parkinsonian signs, especially rigidity, are associated with amnestic mild cognitive impairment. Mild parkinsonian signs and mild cognitive impairment may share similar pathogeneses. Whether this involves Alzheimer-type pathology, Lewy bodies, or vascular changes in the basal ganglia or basal ganglia circuitry deserves further investigation in postmortem studies.

Impact of plasma lipids and time on memory performance in healthy elderly without dementia.

OBJECTIVE: To examine the association of plasma lipid levels to changes in cognitive function in elderly subjects without dementia. METHODS: The authors examined changes in performance in tests of memory, visuospatial/cognitive, and language abilities in 1,147 elderly individuals without dementia or cognitive impairment at baseline followed for 7 years using generalized estimating equations. RESULTS: Performance in all cognitive domains declined significantly over time, while there was no association between levels of any plasma lipid or lipid lowering treatment and memory, cognitive/visuospatial, or language performance at any interval. Higher age at baseline was related to lower scores in all three domains at each interval, while higher education and white ethnicity were associated with higher scores in all domains. Analyses relating plasma lipids to performance in color trails tests using proportional hazards regression showed no association. In subsequent analyses excluding subjects with incident dementia, memory performance declined over time, while cognitive/visuospatial and language performance did not. Higher plasma high density lipoprotein and total cholesterol were associated with higher scores in language performance at baseline; this domain declined faster among individuals with higher total cholesterol, but this result was not significant after taking multiple comparisons into account. Plasma triglycerides, low density lipoprotein, or treatment with lipid lowering agents were not associated with changes in cognitive performance. CONCLUSIONS: Plasma lipid levels or treatment with lipid lowering agents in the elderly were not associated with changes in cognitive function.

Plasma A[beta]40 and A[beta]42 and Alzheimer's disease: relation to age, mortality, and risk.

BACKGROUND: Plasma amyloid [beta]-peptide (A[beta]) 40 and A[beta]42 levels are increased in persons with mutations causing early-onset familial Alzheimer's disease (AD). Plasma A[beta]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. METHODS: The authors measured plasma A[beta]40 and A[beta]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[beta]40 and A[beta]42 levels were repeated in 307 subjects 3 years after baseline. RESULTS: Compared with individuals who never developed AD, patients with AD at baseline and those who developed AD during the follow-up had significantly higher A[beta]42, but not A[beta]40, plasma levels. The risk of AD in the highest quartile of plasma A[beta]42 was increased by more than twofold over that in the lowest quartile. The highest plasma A[beta]42 levels were observed in patients with AD who died during the follow-up. Plasma A[beta]42, but not A[beta]40, levels decreased over time in patients with newly acquired AD. CONCLUSIONS: Plasma A[beta]40 and A[beta]42 increase with age and are strongly correlated with each other. Plasma A[beta]40 and A[beta]42 levels are elevated in some patients before and during the early stages of AD but decline thereafter. High plasma A[beta]42 levels may also be associated with mortality in patients with AD.

Neuropsychological test performance: a study of non-Hispanic White elderly.

This study examined within-group differences in neuropsychological test performance between US versus foreign-born English-speaking White elders. Participants included 193 randomly selected English-speaking elderly community residents who self-identified as non-Hispanic White. Participants were classified as US (n = 106) or foreign-born (n = 87). All participants were independently diagnosed by a physician as nondemented. After controlling for years of education, participants born in the United States obtained significantly higher scores on measures of verbal abstract reasoning, naming, and fluency than foreign-born elders. These results suggest that although non-Hispanics White are often treated as a homogeneous group, performance differences exist even within this group. Effects of acculturation level and language use on cognitive styles may help explain these findings.

Influence of leisure activity on the incidence of Alzheimer's disease.

OBJECTIVE: To determine whether leisure activities modify the risk for incident dementia. BACKGROUND: Although high educational and occupational attainments have been associated with reduced risk of incident dementia, the relation between leisure activities and dementia risk has not been adequately investigated. METHODS: A total of 1,772 nondemented individuals aged 65 years or older, living in northern Manhattan, New York, were identified and followed longitudinally in a community-based cohort incidence study. Subjects' leisure activities at baseline were assessed, annual examinations with the same standardized neurologic and neuropsychological measures were performed for up to 7 years (mean 2.9 years), and incident dementia was assessed as the main outcome measure. Cox proportional hazards models, adjusting for age, ethnic group, education, and occupation, were used to estimate the relative risk (RR) of incident dementia associated with high leisure activities. RESULTS: Of the 1,772 subjects, 207 became demented. The risk of dementia was decreased in subjects with high leisure activities (RR, 0.62; 95% CI 0.46 to 0.83). The association of high leisure with decreased RR of incident dementia was present even when baseline cognitive performance, health limitations interfering with desired leisure activities, cerebrovascular disease, and depression were considered. CONCLUSIONS: The data suggest that engagement in leisure activities may reduce the risk of incident dementia, possibly by providing a reserve that delays the onset of clinical manifestations of the disease.

Dimensions of child maltreatment and children's adjustment: contributions of developmental timing and subtype.

This investigation examined the dimensions of developmental timing, subtype, and severity of maltreatment and their relations with child adaptation. The 814 children who participated in a summer day camp, 492 of whom were maltreated and 322 of whom were nonmaltreated comparison children, were assessed by camp counselors on their internalizing and externalizing symptomatology, aggressive, withdrawn, and cooperative behavior, and on personality dimensions of ego resiliency and ego control, and were rated by peers on disruptive, aggressive, and cooperative behavior. The severity within each subtype of maltreatment and the developmental period in which each subtype occurred were examined through hierarchical regression analyses. Additionally, children with similar timing or subtype patterns were grouped to explore diversity in outcomes. Results highlighted the role of severity of emotional maltreatment in the infancy-toddlerhood period and physical abuse during the preschool period in predicting externalizing behavior and aggression. Severity of physical neglect, particularly when it occurred during the preschool period, was associated with internalizing symptomatology and withdrawn behavior. Additionally, maltreatment during the school-age period contributed significant variance after earlier maltreatment was controlled. Chronic maltreatment, especially with onset during infancy-toddlerhood or preschool periods, was linked with more maladaptive outcomes. The implications of measuring multiple dimensions for improving research in child maltreatment are discussed.

Endogenous estrogen levels and Alzheimer's disease among postmenopausal women.

BACKGROUND: Although several studies have suggested that hormone replacement therapy lowers the risk of AD among postmenopausal women, few studies have evaluated the relationship of endogenous estrogen levels and AD. The current study investigated whether serum estrone and estradiol levels were related to the presence of AD among postmenopausal women not currently taking hormone replacement therapy. METHODS: Using a case-control design, we examined an ethnically diverse sample of postmenopausal women who met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD (n = 50) and nondemented controls (n = 93). All women were participants in a study of aging and dementia and were seen consecutively between August 1997 and October 1998. RESULTS: Patients with AD had lower estradiol (F[1,141] = 8.3, p = 0.005) levels than did normal controls. Patients also had lower estrone levels; however, this comparison did not quite meet significance criteria (F[1,141] = 3.6, p = 0.06). Compared to estradiol levels >20 pg/mL, women with AD were four to six times more likely to have levels <20 pg/mL after adjusting for age, years of education, presence of an APOE-epsilon4 allele, ethnicity, and body mass index. There were no significant differences in frequency of AD among women within different quartiles of estrone after adjusting for potential confounds. CONCLUSIONS: The results of this preliminary case-control study suggest that estradiol levels may decline significantly in women in whom AD develops.

Plasma amyloid beta-peptide 1-42 and incipient Alzheimer's disease.

Mutations in the amyloid precursor protein and presenilin 1 and 2 genes result in elevated plasma levels of the amyloid beta-peptide species terminating at amino acid residue 42 (A beta1-42). In a longitudinal study of unrelated elderly individuals, those who subsequently developed Alzheimer's disease had higher plasma levels of A beta1-42 at entry than did those who remained free of dementia. The results indicate that elevated plasma levels of the released A beta peptide A beta1-42 may be detected several years before the onset of symptoms, supporting that extracellular A beta1-42 plays an important role in the pathogenesis of late-onset Alzheimer's disease.

The influence of smoking on the risk of Alzheimer's disease.

OBJECTIVE: To investigate the relationship between cigarette smoking and Alzheimer's disease (AD) in a prospective community-based study in northern Manhattan. BACKGROUND: Results from previous case-control studies suggest that there is a protective effect of smoking on AD. However, the recent prospective Rotterdam Study found that there was an increased risk of AD for smokers, particularly those without an apolipoprotein E (APOE)-epsilon4 allele. METHODS: The authors examined data from a community-based longitudinal study of local elders residing in northern Manhattan to determine whether tobacco use increases or decreases the risk of AD. Information regarding the frequency of tobacco use was obtained in structured interviews at the baseline assessment. Standardized clinical assessments were subsequently completed on each subject at annual visits during which incident cases of AD were identified. RESULTS: The relative risk (RR) of AD among former smokers was 0.7 (95% CI, 0.5 to 1.1). The RR among current smokers was 1.9 (95% CI, 1.2 to 3.0). Smokers without an APOE-epsilon 4 allele had the highest risk of AD (RR = 2.1; 95% CI, 2.1 to 3.7) compared with those with an APOE-epsilon 4 allele (RR = 1.4; 95% CI, 0.6 to 3.3). CONCLUSIONS: Our results are consistent with the observation that smoking increases the risk of AD. However, we found that among previous smokers who quit smoking, there may be a slight reduction in the risk of AD.

Effect of literacy on neuropsychological test performance in nondemented, education-matched elders.

The current investigation compared neuropsychological test performance among nondemented literate and illiterate elders. The sample included participants in an epidemiological study of normal aging and dementia in the Northern Manhattan community. All participants were diagnosed as nondemented by a neurologist, and did not have history of Parkinson's disease, stroke, or head injury. Literacy level was determined by self-report. MANOVAs revealed a significant overall effect for literacy status (literate vs. illiterate) on neuropsychological test performance when groups were matched on years of education. The overall effect of literacy status remained significant after restricting the analyses to elders with no formal education, and after controlling for the effects of language of test administration. Specifically, illiterates obtained lower scores on measures of naming, comprehension, verbal abstraction, orientation, and figure matching and recognition. However tests of verbal list delayed recall, nonverbal abstraction, and category fluency were unaffected by literacy status, suggesting that these measures can be used to accurately detect cognitive decline among illiterate elders in this sample. Differences in organization of visuospatial information, lack of previous exposure to stimuli, and difficulties with interpretation of the logical functions of language are possible factors that contribute to our findings.

The effect of African-American acculturation on neuropsychological test performance in normal and HIV-positive individuals. The HIV Neurobehavioral Research Center (HNRC) Group.

Two studies were conducted to examine the relationship of acculturation to neuropsychological test performance among (1) medically healthy, neurologically normal African Americans (N = 170); and (2) HIV positive (HIV+) subgroups of African Americans and Whites (Ns = 20) matched on age, education, sex, and HIV disease stage. Acculturation was measured through self report for all participants, and linguistic behavior (Black English use) was assessed in a subset of medically healthy individuals (N = 25). After controlling for the effects of age, education, and sex, medically healthy African Americans who reported less acculturation obtained lower scores on the WAIS-R Information subtest and the Boston Naming Test than did more acculturated individuals. Black English use was associated with poor performance on Trails B and the WAIS-R Information subtest. HIV+ African Americans scored significantly lower than their HIV+ White counterparts on the Category Test, Trails B, WAIS-R Block Design and Vocabulary subtests, and the learning components of the Story and Figure Memory Tests. However, after accounting for acculturation, ethnic group differences on all measures but Story Learning became nonsignificant. These results suggest that there are cultural differences within ethnic groups that relate to neuropsychological test performance, and that accounting for acculturation may improve the diagnostic accuracy of certain neuropsychological tests.

Cognitive test performance among nondemented elderly African Americans and whites.

We examined the neuropsychological test performance of a randomly selected community sample of English-speaking non-Hispanic African American and white elders in northern Manhattan. All participants were diagnosed as nondemented by a neurologist, whose assessment was made independent of neuropsychological test scores. African American elders obtained significantly lower scores on measures of verbal and nonverbal learning and memory, abstract reasoning, language, and visuospatial skill than whites. After using a stratified random sampling technique to match groups on years of education, many of the discrepancies became nonsignificant; however, significant ethnic group differences on measures of figure memory, verbal abstraction, category fluency, and visuospatial skill remained. Discrepancies in test performance of education-matched African Americans and whites could not be accounted for by occupational attainment or history of medical conditions such as hypertension and diabetes. These findings emphasize the importance of using culturally appropriate norms when evaluating ethnically diverse elderly for dementia.

[Leu]enkephalin enhances active avoidance conditioning in rats and mice.

The effects of intraperitoneal (IP) administration of the endogenous opioid peptide, [Leu]enkephalin (LE), on avoidance conditioning in rodents were investigated. At a dose of 30 micrograms/kg (IP), LE enhanced acquisition of a one-way step-through active avoidance response when administered 2 minutes before training to Swiss Webster mice. [Leu]enkephalin produced a U-shaped dose-response function because both lower and higher doses of LE did not affect avoidance responding. [Leu]enkephalin-induced enhancement of avoidance acquisition was also observed in Sprague-Dawley rats; the intraperitoneal injection of 10 micrograms/kg LE, administered 5 minutes before training, enhanced acquisition of a jump-up one-way active avoidance response. When administered to Sprague-Dawley rats immediately after training, LE (30 micrograms/kg IP) enhanced jump-up avoidance responding at test 24 hours after peptide injection. Previously, we found LE to impair acquisition in the same tasks in both rats and mice, also at microgram doses, and also in a U-shaped manner. Thus, LE can either enhance or impair learning within the same species and the same task; these findings are in agreement with recent theoretical proposals regarding the nature of compounds, such as LE, that modulate learning and memory.