The influence of apolipoprotein E genotype on visuospatial attention dissipates after age 80.

Although it is established that apolipoprotein E (APOE) e4 allele increases the risk of Alzheimer's disease (AD), epidemiological studies indicate that genetic risk decreases late in life. This raises the question of whether the effects of APOE on cognition that are seen in midlife arise from a cognitive phenotype of APOE or from the presence of early AD in some APOE-e4 carriers. The authors addressed this question by comparing the cognitive consequences of variation in the APOE gene between individuals over the age of 80 (old-old) and middle-aged and young-old individuals. A spatially cued discrimination paradigm--previously shown to be sensitive to AD and to APOE genotype--required a speeded categorization of a target letter following cues that were valid, invalid, or neutral in predicting target location. Results revealed greater costs of invalid cues in the APOE-e4 carriers of middle-aged and young-old, but not old-old, groups. The dissipation of the APOE effect in old-old individuals at lower risk of AD suggests that visuospatial attention impairments seen as early as midlife in APOE-e4 carriers may be a preclinical marker of AD.

Functional magnetic resonance imaging and magnetoencephalography differences associated with APOEepsilon4 in young healthy adults.

Functional neural alterations are present in middle-aged to late-aged healthy individuals carrying the epsilon4 allele of the apolipoprotein E (APOEepsilon4) gene, a known risk factor for Alzheimer's disease. Neural activity was measured in young adults with and without the epsilon4 allele (APOEepsilon4+ and APOEepsilon4-) by functional magnetic resonance imaging and magnetoencephalography while performing a visual working memory task on two separate days. Greater activity was observed in frontal areas and cingulate gyri in APOEepsilon4+ participants by both functional magnetic resonance imaging and magnetoencephalography with regional blood oxygenation level-dependent responses correlating with increased theta band power. The findings suggest that the presence of the APOEepsilon4 allele has physiological consequences before aging that may contribute to risk for Alzheimer's disease.

Biomarkers in the diagnosis of Alzheimer's disease: are we ready?

Although clinical manifestations of cognitive dysfunction and impairments of activities of daily living are the current standard measures for the diagnosis of Alzheimer's disease, biomarkers are receiving increasing attention in research centers as possible early diagnostic measures or as surrogate measures of the ongoing pathology. In preparation for the upcoming development of the Diagnostic and Statistical Manual of Mental Disorders (5th ed; DSM-V) nosology, the American Psychiatric Association has sponsored an effort to reassess the current approaches to diagnosis in dementia in general and Alzheimer's disease in particular. This article focuses on the potential use of biomarkers in the diagnosis of Alzheimer's disease, in the monitoring of mild cognitive impairment, and as possible prognostic markers in normal controls at risk for dementia. Most advanced information is available with the biomarkers found in the cerebrospinal fluid, but there are many other potential biomarkers using blood, brain imaging, or a combination. The current biomarker approaches to diagnosis are reviewed along with a special emphasis on near-term recommendations and further research directions.

The use of biomarkers in the elderly: current and future challenges.

Biomarkers are hypothesized but not frequently used in research with the elderly because of a general paucity of supportive scientific data. However, there is an obvious need for greater diagnostic specificity and sensitivity across many diagnoses in the elderly, as well as good targets for therapeutic trials. The authors reviewed the available information in this field as part of a general review of geriatric research for the . Potential biomarkers with pathophysiologic significance have been studied in the field of Alzheimer disease research with some success, especially in the area of genetic markers (apolipoprotein E [APOE] epsilon4 allele), neuroimaging, and cerebrospinal fluid markers (beta-amyloid and tau). While some progress has been made in the search for adequate biomarkers in the elderly, in particular with Alzheimer disease, much more work is needed before these potential biomarkers can be reliably used in clinical practice.

Mood disorders in the medically ill: scientific review and recommendations.

OBJECTIVE: The purpose of this review is to assess the relationship between mood disorders and development, course, and associated morbidity and mortality of selected medical illnesses, review evidence for treatment, and determine needs in clinical practice and research. DATA SOURCES: Data were culled from the 2002 Depression and Bipolar Support Alliance Conference proceedings and a literature review addressing prevalence, risk factors, diagnosis, and treatment. This review also considered the experience of primary and specialty care providers, policy analysts, and patient advocates. The review and recommendations reflect the expert opinion of the authors. STUDY SELECTION/DATA EXTRACTION: Reviews of epidemiology and mechanistic studies were included, as were open-label and randomized, controlled trials on treatment of depression in patients with medical comorbidities. Data on study design, population, and results were extracted for review of evidence that includes tables of prevalence and pharmacological treatment. The effect of depression and bipolar disorder on selected medical comorbidities was assessed, and recommendations for practice, research, and policy were developed. CONCLUSIONS: A growing body of evidence suggests that biological mechanisms underlie a bidirectional link between mood disorders and many medical illnesses. In addition, there is evidence to suggest that mood disorders affect the course of medical illnesses. Further prospective studies are warranted.

Apolipoprotein E and category fluency: evidence for reduced semantic access in healthy normal controls at risk for developing Alzheimer's disease.

Two groups of non-demented individuals, who differed on genetic risk for Alzheimer's disease (AD) based on their apolipoprotein E (APOE) genotype, were tested on a category fluency task. Twenty varepsilon4 carriers and twenty varepsilon4 non-carriers were tape recorded while saying animal names for ten minutes. Five measures were examined: total names generated; total clusters; mean cluster size; mean within-cluster retrieval time; and mean between-cluster retrieval time. Groups were matched on age and education and scored as normal on a battery of psychometric tests. The varepsilon4 carriers generated significantly fewer names and clusters, and took significantly longer to access clusters, when compared to the varepsilon4 non-carriers. No group differences were found for cluster size or within-cluster retrieval times. We previously reported [Rosen, V. M., Bergeson, J. L., Putnam, K., Harwell, A., Sunderland, T. (2002). Working memory and apolipoprotein E: What's the connection? Neuropsychologia 40, 2226-2233] that the varepsilon4 carriers in the present study scored significantly lower than the varepsilon4 non-carriers on a measure of working memory/attentional capacity [Operation Span Task, see Turner, M. L., Engle, R. W. (1989). Is working memory capacity task dependent? Journal of Memory and Language 28, 127-154]. In the present study, a significant negative relationship found between span performance and between-cluster retrieval times suggested that reduced attentional capacity may have negatively impacted semantic access for the varepsilon4 carriers. Finally, we found significant relationships between a Trail Making Test [Reitan, R. M. (1992). Trail Making Test, manual for administration and scoring. Tucson, AZ: Reitan Neuropsychology Laboratory] "switch" measure (Form B-Form A) and three of the five fluency measures. The findings suggested that the varepsilon4 carrier's reduced attentional capacity may have interfered with their covertly shifting attention among subcategories in the fluency task, resulting in fewer names and clusters generated and longer times to access clusters.

A magnetoencephalography spatiotemporal analysis of neural activities during feature binding.

Previous literature shows that feature binding processes elicit fronto-hippocampal areas. The time course of this process, however, remains unknown. This is the first study that investigates feature binding using magnetoencephalography. Synthetic aperture magnetometry analysis was used to localize sources of increased power in the theta band during the encoding phases of a feature-binding task in the left and right medial frontal gyri (Brodmann's area 10) and left and right anterior cingulate gyri. Theta band synchronization was observed in many of these same areas, but also in other areas not noted to have increased theta band power suggesting a broad network of regions subserving the encoding phase of feature binding.

Depression and Bipolar Support Alliance consensus statement on the unmet needs in diagnosis and treatment of mood disorders in late life.

OBJECTIVES: To review progress made during the past decade in late-life mood disorders and to identify areas of unmet need in health care delivery and research. PARTICIPANTS: The Consensus Development Panel consisted of experts in late-life mood disorders, geriatrics, primary care, mental health and aging policy research, and advocacy. EVIDENCE: (1) Literature reviews addressing risk factors, prevention, diagnosis, treatment, and delivery of services and (2) opinions and experiences of primary care and mental health care providers, policy analysts, and advocates. CONSENSUS PROCESS: The Consensus Development Panel listened to presentations and participated in discussions. Workgroups considered the evidence and prepared preliminary statements. Workgroup leaders presented drafts for discussion by the Consensus Development Panel. The final document was reviewed and edited to incorporate input from the entire Consensus Development Panel. CONCLUSIONS: Despite the availability of safe and efficacious treatments, mood disorders remain a significant health care issue for the elderly and are associated with disability, functional decline, diminished quality of life, mortality from comorbid medical conditions or suicide, demands on caregivers, and increased service utilization. Discriminatory coverage and reimbursement policies for mental health care are a challenge for the elderly, especially those with modest incomes, and for clinicians. Minorities are particularly underserved. Access to mental health care services for most elderly individuals is inadequate, and coordination of services is lacking. There is an immediate need for collaboration among patients, families, researchers, clinicians, governmental agencies, and third-party payers to improve diagnosis, treatment, and delivery of services for elderly persons with mood disorders.

Increased levels of CSF phosphorylated tau in apolipoprotein E epsilon4 carriers with mild cognitive impairment.

We investigated the correlation between the apolipoprotein E varepsilon4 allele (apoE epsilon4) carrier status, a major risk factor of Alzheimer's disease (AD), and levels of tau protein phosphorylated at threonine 231 (P-tau(231P)) in cerebrospinal fluid (CSF) in predementia and clinical stages of AD and healthy controls (HC). Thirty-one subjects with mild cognitive impairment (MCI) who had converted to AD during follow-up were included, as well as 71 AD patients, and 29 HC subjects. In MCI, but not in AD and HC, CSF P-tau(231P) levels were significantly higher in apoE epsilon4 carriers compared to non-carriers (p<0.001). Controlling for disease duration, the apoE epsilon4 effect on P-tau(231P) remained significant. Our study indicates that the apoE epsilon4 carrier status should be considered when CSF P-tau(231P) is evaluated as biomarker candidate of AD in MCI subjects.

Scaling of visuospatial attention undergoes differential longitudinal change as a function of APOE genotype prior to old age: results from the NIMH BIOCARD study.

The effect of apolipoprotein E (APOE) genotype on longitudinal cognitive decline in midlife was investigated with attentional scaling. Healthy individuals (mean age 59.6 years) genotyped for APOE were tested at 3 12-month intervals on a cued visual search task. A random effects model revealed significant interaction in effect of precue size on search speed between APOE-epsilon4 gene dose and assessment, with longitudinal increases in noncarriers and heterozygotes but longitudinal decreases in homozygotes. Association of APOE-epsilon4 with cognitive decline in midlife is consistent with an Alzheimer's disease (AD) prodrome, albeit a decade or more before average age of AD diagnosis. However, cognitive decline in midlife associated with a gene modulating neuronal response to insult argues that the concept of an AD prodrome includes factors that allow as well as cause AD.

Effects of apolipoprotein E genotype on spatial attention, working memory, and their interaction in healthy, middle-aged adults: results From the National Institute of Mental Health's BIOCARD study.

The cognitive consequences of the apolipoprotein E-epsilon4 (APOE-epsilon4) allele were examined in middle age, before likely onset of symptoms of Alzheimer's disease. The authors identified 3 cognitive processes--visuospatial attention, spatial working memory, and the effect of visuospatial attention on working memory--and devised "behavioral assays" of the integrity of components of these processes. Redirecting visuospatial attention, retention of memory for location, and attentional modulation of memory of target location were affected by APOE genotype. Visuospatial attention showed additive effects of epsilon4 gene dose; each additional epsilon4 allele inherited further slowed disengagement from invalidly cued space. In contrast, working memory performance was affected only in epsilon4 homozygotes. Effect sizes for the APOE gene were moderate to large, ranging from 14% to 24%. Effects of APOE genotype on component processes of cognition in healthy, middle-aged adults is consistent with the emergence in adulthood of an APOE-epsilon4 cognitive phenotype.

Cerebrospinal fluid beta-amyloid1-42 and tau in control subjects at risk for Alzheimer's disease: the effect of APOE epsilon4 allele.

BACKGROUND: Cerebrospinal fluid (CSF) measures of beta-amyloid(1-42) and tau are linked with the known neuropathology of Alzheimer's disease (AD). Numerous lines of evidence have also suggested that individuals with at least one APOE epsilon4 allele on chromosome 19 are at increased risk of developing AD. We tested these CSF markers in groups of subjects with AD and healthy older control subjects, using the absence or presence of the APOE epsilon4 allele as a predictive variable in the search for possible prognostic biomarkers of AD. METHODS: We assessed the levels of beta-amyloid(1-42) and total tau in the CSF of 292 subjects (142 control subjects and 150 subjects with mild-to-moderate AD), who were research participants at the National Institute of Mental Health. The group of control subjects was enriched with a high percentage of subjects with a positive family history of AD. All subjects underwent extensive global cognitive testing. RESULTS: When divided according to the absence or presence of the APOE epsilon4 allele, the control subjects with at least one epsilon4 allele had significantly lower CSF beta-amyloid(1-42) but not tau levels than control subjects without an APOE epsilon4 allele (p < .01). As expected, the AD patients had lower levels of CSF beta-amyloid(1-42) and higher CSF tau levels than the normal control group (p < .01). CONCLUSIONS: The association of APOE epsilon4 allele and lower, more AD-like levels of CSF beta-amyloid(1-42) in older control subjects is consistent with previous studies showing possible neuroimaging and cognitive abnormalities with epsilon4 carriers and suggests that CSF beta-amyloid(1-42) decreases might represent an early biomarker of AD. Longitudinal follow-up is of course required to verify whether this biomarker is indeed predictive of clinical conversion to AD.

Views of potential subjects toward proposed regulations for clinical research with adults unable to consent.

OBJECTIVE: The authors' goal was to assess healthy individuals' attitudes toward five of the most prominent proposed safeguards regarding the consent process for research with adults unable to consent. METHOD: Telephone interviews were conducted with 246 individuals with a family history of Alzheimer's disease who had participated in clinical research. RESULTS: The majority of respondents said that they were willing to participate in research if they lost the ability to consent. Few completed a research advance directive. Many had discussed their preferences with their families, and the majority would allow their families to make research decisions for them. CONCLUSIONS: Enrolling individuals who are unable to consent in research that offers no potential for medical benefit is consistent with the preferences of at least some individuals. This suggests that such research should not be prohibited, provided there is sufficient evidence that it is consistent with the preferences of individual subjects. Requiring that such evidence be provided in a formal research advance directive may be unnecessarily restrictive. More research is needed to assess whether the findings in this group of subjects generalize to other groups.

A collaborative study of the emergence and clinical features of the major depressive syndrome of Alzheimer's disease.

OBJECTIVE: This report provides a description of the prevalence and clinical features of the major depressive syndrome of Alzheimer's disease using data derived from structured diagnostic assessments of 243 patients with probable Alzheimer's disease and 151 nondemented elderly comparison subjects. METHOD: Subjects were characterized by a consortium of four Alzheimer's disease research centers and the Geriatric Psychiatry Branch of the National Institute of Mental Health. All sites administered the Clinical Assessment of Depression in Dementia, a structured, anchored diagnostic interview that was developed to reliably diagnose and characterize major depressive episodes in this population. RESULTS: Despite the use of a common, reliable methodology for the assessment and diagnosis of major depressive episodes, the prevalence of major depression in Alzheimer's disease ranged widely from 22.5% to 54.4% across the recruitment sites. The prevalence of major depressive episodes among Alzheimer's disease patients in the aggregate sample exceeded that for elderly comparison subjects and reached nearly 50% among the most severely demented patients. Alzheimer's disease patients with a current major depressive episode had earlier mean ages at onset, a higher mean Hamilton Depression Rating Scale score, and were more likely to be experiencing psychotic symptoms than those who had not developed a major depressive episode. Although the major depressive episodes of Alzheimer's disease patients and nondemented elderly comparison subjects included similar numbers of depressive symptoms, patients with Alzheimer's disease were more likely to report a diminished ability to concentrate or indecisiveness and less likely to experience sleep disturbances and feelings of worthlessness or excessive guilt during their major depressive episodes. None of the clinical features of major depression differed significantly in frequency among depressed Alzheimer's disease patients with mild, moderate, or severe dementia. Concurrent psychotic symptoms progressively increased with dementia severity. CONCLUSIONS: The high rate of major depressive episodes that occur after the onset of cognitive impairment among patients with Alzheimer's disease (the majority of whom had no premorbid history of major depression), common emergence in the early stages of dementia when symptoms of cognitive impairment are least likely to contribute to the syndromal diagnosis of major depression, and differences in the clinical presentations of the major depressive episodes of Alzheimer's disease patients and nondemented elderly comparison subjects, all support the validity of the major depressive syndrome of Alzheimer's disease. Our findings suggest that the major depressive syndrome of Alzheimer's disease may be among the most common mood disorders of older adults.

The apolipoprotein E gene, attention, and brain function.

The epsilon4 allele of the apolipoprotein E (ApoE) gene is associated with alterations in brain function and is a risk factor for Alzheimer's disease (AD). Changes in components of visuospatial attention with ApoE-epsilon4, aging, and AD are described. Healthy middle-aged adults without dementia who have the ApoE-epsilon4 gene show deficits in spatial attention and working memory that are qualitatively similar to those seen in clinically diagnosed AD patients. The findings support an association between ApoE polymorphism and specific components of visuospatial attention. Molecular mechanisms that may mediate the ApoE-attention link by modulating cholinergic neurotransmission to the posterior parietal cortex are discussed. Studies of attention and brain function in ApoE-epsilon4 carriers without dementia can advance knowledge of the genetics of visual attention, may enhance understanding of the preclinical phase of AD, and may lead to better methods for early AD detection.

Reminiscence group activities and discourse interaction in Alzheimer's disease.

Reminiscence is an enriching and complex experience having many purposes and functions when used with patients with Alzheimer's disease (AD). Discourse is a component of language that has been shown to decline in patients with AD (Mentis, Briggs-Whittaker, & Gramigna, 1995). This article represents one of the first studies to examine the effects of reminiscence group (RG) activities on discourse interactions in patients with AD. This article specifically addresses the AD population within a RG setting. Observations suggested that objective ratings of conversational discourse would be better (less impaired) in patients with AD when obtained in relatively unstructured environments (e.g., during RG activity) as compared to ratings obtained in conversational environments imposing more structure (e.g., a session in which language function was being evaluated). Comparisons made of conversational and narrative discourse skills observed during different testing environments in patients with AD revealed predicted outcomes. That is, discourse elicited in an environment that was less structured yielded qualitatively better discourse patterns, particularly related to selecting and maintaining a topic, requesting additional information about a topic, changing a topic during conversation, and turn-taking. Results are discussed in terms of their relevance to gerontological nurses managing patients with AD.

Failing compensatory mechanisms during working memory in older apolipoprotein E-epsilon4 healthy adults.

How and when the known genetic risk allele, apolipoprotein E-epsilon4 (APOEepsilon4), confers risk to Alzheimer's disease has yet to be determined. We studied older adults and found that APOEepsilon4 carriers had greater neural activation in the medial frontal and parahippocampal gyrus during a memory task (cluster-corrected p < .01). When compared to a group of younger adults, interactive effects of age and APOEepsilon4 were found in the inferior frontal-anterior temporal region, one of the first areas to develop amyloid plaques in patients with Alzheimer's disease, and, in the posterior cingulate, one of the earliest areas to show decreased cerebral metabolism in Alzheimer's disease. Thus, abnormally high activation in fronto-temporal areas are present in both younger and older APOEepsilon4 carriers confronted with a working memory task when compared to non-APOEepsilon4 carriers. This effect, however, appears to diminish with age.