Following are short descriptions of recent research on Alzheimer's disease. Keep in mind that hundreds of articles on Alzheimer's disease are published each month. The articles listed below are a few that have sparked our interest. We will be adding new research summaries and hope you will revisit our site to learn what is new on Alzheimer's disease. New research on the treatment of Alzheimer's disease is in the treatment section of this web site.

Education and reported onset of symptoms among individuals with Alzheimer disease. Roe CM, Xiong C, Grant E, et al. Archives of Neurology, 65(1):108-111, 2008

OBJECTIVES: To examine whether reported age at onset of dementia symptoms among participants with Alzheimer disease (AD) is later for those with fewer years of education and, if so, to see if education is attributed to delayed detection of symptoms. DESIGN: Case series. SETTING: National Alzheimer's Coordinating Center Minimum Data Set (N = 21,880 participants) and Washington University Alzheimer's Disease Research Center (N = 1,449 participants). RESULTS: Reported age at onset of dementia symptoms is slightly younger in participants with more education. Participants with fewer years of education show greater clinical severity of Alzheimer disease at first assessment. CONCLUSION: Symptoms of Alzheimer disease are recognized later among those with less education.

Neuropsychological strategies for detecting early dementia. Grober E, Hall C, McGinn M, et al. Journal of the International Neuropsychological Society, 14(1):130-142, 2008

As new and more effective treatments for Alzheimer's disease (AD) emerge, the development of efficient screening strategies in educationally and racially diverse primary care settings has increased in importance. A set of candidate screening tests and an independent diagnostic assessment were administered to a sample of 318 patients treated at a geriatric primary care center. Fifty-six subjects met criteria for dementia. Exploratory analysis led to the development of three two-stage screening strategies that differed in the composition of the first stage or Rapid Dementia Screen, which is applied to all patients over the age of 65. The second stage, applied to those patients who screen positively for dementia, is accomplished with the Free and Cued Selective Reminding Test to detect memory impairment. Using clinical diagnosis as a gold standard, the strategies had high sensitivity and specificity for identifying dementia and performed better for identifying AD than non-AD dementias. Sensitivity and specificity did not differ by race or education. The strategies provide an efficient approach to screening for early dementia.

Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer’s disease. Rojo LE, Fernandez JA, Maccioni AA, et al. Archives of Medical Research, 39(1):1-16, 2008

During the past few years, an increasing set of evidence has supported the major role of deregulation of the interaction patterns between glial cells and neurons in the pathway toward neuronal degeneration. Neurons and glial cells, together with brain vessels, constitute an integrated system for brain function. Inflammation is a process related with the onset of several neurodegenerative disorders, including Alzheimer's disease (AD). Several hypotheses have been postulated to explain the pathogenesis of AD, but none provides insight into the early events that trigger metabolic and cellular alterations in neuronal degeneration. The amyloid hypothesis was sustained on the basis that Abeta-peptide deposition into senile plaques is responsible for neurodegeneration. However, recent findings point to Abeta oligomers as responsible for synaptic impairment in neuronal degeneration. Amyloid is only one among many other major factors affecting the quality of neuronal cells. Another explanation derives from the tau hypothesis, supported by the observations that tau hyperphosphorylations constitute a common feature of most of the altered signaling pathways in degenerating neurons. Altered tau patterns have been detected in the cerebrospinal fluids of AD patients, and a close correlation was observed between the levels of hyperphosphorylated tau isoforms and the degree of cognitive impairment. On the other hand, the anomalous effects of cytokines and trophic factors share in common the activation of tau hyperphosphorylation patterns. In this context, a neuroimmunological approach to AD becomes relevant. When glial cells that normally provide neurotrophic factors essential for neurogenesis are activated by a set of stressing events, they overproduce cytokines and NGF, thus triggering altered signaling patterns in the etiopathogenesis of AD. A solid set of discoveries has strengthened the idea that altered patterns in the glia-neuron interactions constitute early molecular events within the cascade of cellular signals that lead to neurodegeneration in AD. A direct correlation has been established between the Abeta-induced neurodegeneration and cytokine production and its subsequent release. In effect, neuroinflammation is responsible for an abnormal secretion of proinflammatory cytokines that trigger signaling pathways that activate brain tau hyperphosphorylation in residues that are not modified under normal physiological conditions. Other cytokines such as IL-3 and TNF-alpha seem to display neuroprotective activities. Elucidation of the events that control the transitions from neuroprotection to neurodegeneration should be a critical point toward elucidation of AD pathogenesis.

Education, cognitive function, and severity of neuropathology in Alzheimer disease. Koepsell TD, Kurland BF, Harel O, et al. Neurology, December 2007 [Epub ahead of print]

BACKGROUND: Education may modulate the degree to which the neuropathology of Alzheimer disease (AD) is expressed as impaired cognitive performance. METHODS: We studied 2,051 participants age 65+ years at 27 AD Centers who died and underwent autopsy. All took the Mini-Mental State Examination (MMSE) within 2 years before death. Braak & Braak stage, neuritic plaque density, and Consortium to Establish a Registry for Alzheimer's Disease and National Institute on Aging (NIA)/Reagan diagnostic classifications quantified AD neuropathologic severity. Multivariate analyses modeled MMSE in relation to education and neuropathologic severity, adjusting for age at death, Lewy body pathology, and vascular dementia. RESULTS: Higher education was associated with higher MMSE scores when AD neuropathology was absent or mild. But with more advanced neuropathology, differences in MMSE scores among education levels were attenuated. For example, among patients without AD by NIA/Reagan criteria, fitted MMSE scores ranged from 19.6 for patients with less than high school education to 25.9 with education beyond high school. But among patients with neuropathologically advanced AD, the range of scores by education was only 7.1 to 8.6. CONCLUSIONS: We found no evidence of larger education-related differences in cognitive function when Alzheimer disease (AD) neuropathology was more advanced. Higher Mini-Mental State Examination scores among more educated persons with mild or no AD may reflect better test-taking skills or cognitive reserve, but these advantages may ultimately be overwhelmed by AD neuropathology.

The genetics of very early onset Alzheimer disease. Filley CM, Rollins YD, Anderson CA, et al. Cognitive and Behavioral Neurology, 20(3):149-156, 2007

OBJECTIVE: This study was undertaken to clarify the genetics of very early onset Alzheimer disease (VEOAD), defined as AD beginning before age 35. BACKGROUND: Early onset AD (EOAD) is defined by onset of symptoms before age 65, and affected individuals may harbor a mutation in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein. VEOAD is exceedingly rare, and PSEN1 mutations have been implicated. We encountered a man with phenotypic frontotemporal dementia beginning at age 32 and a strong family history of an autosomal dominant dementia who was found at autopsy to have AD. METHODS: Histologic and genetic analyses of the patient's brain were undertaken, and a review of all published VEOAD cases was performed. RESULTS: Histologic findings were diagnostic of advanced stage AD. Genetic evaluation of brain tissue identified an intronic PSEN1 polymorphism; no known pathogenic mutation was found. Literature review (1934 to 2007) disclosed 101 cases of VEOAD; the youngest age of dementia onset was 24 years. In all cases in which definitive genetic analysis was available, either a PSEN1 mutation or linkage to chromosome 14 was found. CONCLUSIONS: VEOAD can present with atypical clinical features, including findings suggestive of frontotemporal dementia. All reported cases of VEOAD with conclusive genetic analysis seem to be associated with PSEN1 mutations. Genetic testing in adults younger than 35 with dementia can identify the genetic defect and assist in diagnosis and family counseling.

Neuropsychiatric syndromes in dementia. Results from the European Alzheimer Disease Consortium: part I. Aalten P, Verhey FR, Boziki M, et al. Dementia and Geriatric Cognitive Disorders, 24(6):457-463, 2007

BACKGROUND/AIMS: The aim of this study was to identify neuropsychiatric subsyndromes of the Neuropsychiatric Inventory in a large sample of outpatients with Alzheimer's disease (AD). METHODS: Cross-sectional data of 2,354 patients with AD from 12 centres from the European Alzheimer's Disease Consortium were collected. Principal component analysis was used for factor analysis. RESULTS: The results showed the presence of 4 neuropsychiatric subsyndromes: hyperactivity, psychosis, affective symptoms and apathy. The subsyndrome apathy was the most common, occurring in almost 65% of the patients. CONCLUSION: This large study has provided additional robust evidence for the existence of neuropsychiatric subsyndromes in AD.

Rates of depression in individuals with pathologic but not clinical Alzheimer disease are lower than those in individuals without the disease: findings from the Baltimore Longitudinal Study on Aging (BLSA). Morgan MD, Mielke MM, O’Brien R, et al. Alzheimer Disease and Associated Disorders, 21(3):199-204, 2007

The prevalence of major depression is increased in Alzheimer disease (AD), but currently the basis of this association remains unclear. The present study examined rates of depression in 4 groups of participants with postmortem examination from the Baltimore Longitudinal Study of Aging: (1) cognitively normal controls with no Alzheimer pathology, (2) cognitively normal individuals with Alzheimer pathology, (3) individuals with mild cognitive impairment plus Alzheimer pathology, (4) individuals with clinical diagnoses of dementia plus Alzheimer pathology. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. Individuals with Alzheimer pathology but no cognitive decline before death had significantly lower rates of depression than cognitively normal controls with no Alzheimer pathology and individuals with Alzheimer pathology plus clinical diagnoses of dementia. These findings suggest that depression is a risk factor for AD in the presence of AD pathology, but depression is not a risk factor for AD pathology.

Neurogenesis in the adult brain: implications for Alzheimer’s disease. Galvan V, Bredesen DE. CNS and Neurological Disorders Drug Targets, 6(5):303-310, 2007

The function of neurogenesis in the adult brain is still unknown. Interventions such as environmental enrichment and exercise impinge on neurogenesis, suggesting that the process is regulated by experience. Conversely, a role for neurogenesis in learning has been proposed through 'cellular plasticity', a process akin to synaptic plasticity but operating at the network level. Although neurogenesis is stimulated by acute injury, and possibly by neurodegenerative processes such as Alzheimer's disease (AD), it does not suffice to restore function. While the role and direction of change in the neurogenic response at different stages of AD is still a matter of debate, it is possible that a deficit in neurogenesis may contribute to AD pathogenesis since at least one of the two regions ostensibly neurogenic in the adult human brain (the subgranular zone of the dentage gyrus and the ventriculo-olfactory neurogenic system) support high-level functions affected in early AD (associative memory and olfaction respectively). The age of onset and the rate of progression of sporadic forms of AD are highly variable. Sporadic AD may have a component of insufficient neurogenic replacement or insufficient neurogenic stimulation that is correlated with traits of personal history; the rate of neurogenesis and the survival of replicating progenitors is strongly modified by behavioral interventions known to impinge on the rate of neurogenesis and the probability of survival of newly born neurons - exercise, enriched experience, and learning. This view is consistent with epidemiological data suggesting that higher education and increased participation in intellectual, social and physical aspects of daily life are associated with slower cognitive decline in healthy elderly ("cognitive reserve") and may reduce the risk of AD. Although neurogenesis can be modulated exogenously by growth factors, stimulation of neurogenesis as a mean to treat neurodegeneration is still for the most part speculative. Moreover, it is possible that different roles of neurogenesis during the course of AD are dictated by the degree of permissibility of the environment in which the process is taking place. A unique opportunity may exist in which the therapeutic stimulation of neurogenesis might contribute to functional 'repair' of the adult diseased brain, before damage to whole neuronal networks has ensued. In spite of the considerable gaps in our knowledge of neurogenesis, and of the considerable limitations that will need to be overcome before we can intervene in the process, that new neurons are added continuously to the adult mammalian brain is a discovery that has already changed the way we think about neurobiology, and may soon change the way we understand and approach neurodegenerative diseases such as AD.

TNFR-associated factor-2 (TRAF-2) in Alzheimer’s disease. Culpan D, Cram D, Chalmers K, et al. Neurobiology of Aging, December 2007 [Epub ahead of print]

Levels of tumor necrosis factor-alpha (TNF-alpha) are increased in the brain in Alzheimer's disease (AD). The TNF-alpha/TNF-R signaling pathways involve complex interactions between several proteins, including TNF-receptor-associated factor-2 (TRAF-2). We have examined the distribution and levels of TRAF-2 in AD and control brains and also whether single nucleotide polymorphisms (SNPs) in the TRAF-2 gene are associated with AD and influence TRAF-2 expression. Immunohistochemistry demonstrated TRAF-2 in AD and control cortex in neurons, within plaque-associated neurites and some neurofibrillary tangles. Western blots revealed a band of the expected apparent molecular mass ( approximately 50kDa) for TRAF-2, in homogenates of AD and control cortex. RT-PCR showed the levels of TRAF-2 mRNA to be significantly higher in the frontal cortex of AD than control brains (p=0.015). TRAF-2 mRNA expression was not linked to any SNPs. The 3' UTR SNP (rs7852970) GG allele was significantly protective against AD (p=0.030). Our findings suggest that the TRAF-2 pathway is involved AD. The mechanisms are currently unclear and need further examination.

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