I have developed "tennis elbow" from lugging this book around the past four weeks, but it is worth the pain, the effort, and the aspirin. It is also worth the (relatively speaking) bargain price. Including appendixes, this book contains 894 pages of text. The entire panorama of the neural sciences is surveyed and examined, and it is comprehensive in its scope, from genomes to social behaviors. The editors explicitly state that the book is designed as "an introductory text for students of biology, behavior, and medicine," but it is hard to imagine any audience, interested in any fragment of neuroscience at any level of sophistication, that would not enjoy this book. The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or

Principles of Neural Science

Inflammation and Alzheimer's disease.

Summary Currently available evidence strongly supports the position that the initiating event in Alzheimer's disease (AD) is related to abnormal processing of β-amyloid (Aβ) peptide, ultimately leading to formation of Aβ plaques in the brain. This process occurs while individuals are still cognitively normal. Biomarkers of brain β-amyloidosis are reductions in CSF Aβ 42 and increased amyloid PET tracer retention. After a lag period, which varies from patient to patient, neuronal dysfunction and neurodegeneration become the dominant pathological processes. Biomarkers of neuronal injury and neurodegeneration are increased CSF tau and structural MRI measures of cerebral atrophy. Neurodegeneration is accompanied by synaptic dysfunction, which is indicated by decreased fluorodeoxyglucose uptake on PET. We propose a model that relates disease stage to AD biomarkers in which Aβ biomarkers become abnormal first, before neurodegenerative biomarkers and cognitive symptoms, and neurodegenerative biomarkers become abnormal later, and correlate with clinical symptom severity.

/pdf/hypothetical-model-of-dynamic-biomarkers-of-the-alzheimer-s-5azt2w7laa.pdf

Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade

Objective. —To examine more closely the association between apolipoprotein E (APOE) genotype and Alzheimer disease (AD) by age and sex in populations of various ethnic and racial denominations. Data Sources. —Forty research teams contributed data onAPOEgenotype, sex, age at disease onset, and ethnic background for 5930 patients who met criteria for probable or definite AD and 8607 controls without dementia who were recruited from clinical, community, and brain bank sources. Main Outcome Measures. —Odds ratios (ORs) and 95% confidence intervals (Cls) for AD, adjusted for age and study and stratified by major ethnic group (Caucasian, African American, Hispanic, and Japanese) and source, were computed forAPOEgenotypes ∈2/∈2,∈2/∈3,∈2/∈4,∈3/∈4 and ∈4/∈4 relative to the ∈3/∈3 group. The influence of age and sex on the OR for each genotype was assessed using logistic regression procedures. Results. —Among Caucasian subjects from clinic- or autopsy-based studies, the risk of AD was significantly increased for people with genotypes ∈2/∈4 (OR=2.6, 95% Cl=1.6-4.0), ∈3/∈4 (OR=3.2, 95% Cl=2.8-3.8), and ∈4/∈4 (OR=14.9, 95% CI=10.8-20.6); whereas, the ORs were decreased for people with genotypes ∈2/∈2 (OR=0.6, 95% Cl=0.2-2.0) and ∈2/∈3 (OR=0.6, 95% Cl=0.5-0.8). TheAPOE∈4-AD association was weaker among African Americans and Hispanics, but there was significant heterogeneity in ORs among studies of African Americans (P Conclusions. —TheAPOE∈4 allele represents a major risk factor for AD in all ethnic groups studied, across all ages between 40 and 90 years, and in both men and women. The association betweenAPOE∈4 and AD in African Americans requires clarification, and the attenuated effect ofAPOE∈4 in Hispanics should be investigated further.

https://jamanetwork.com/journals/jama/articlepdf/418446/jama_278_16_041.pdf

Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease: A Meta-analysis

Summary In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimer's disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid β (Aβ) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Aβ pathophysiology can accelerate antecedent limbic and brainstem tauopathy.

/pdf/tracking-pathophysiological-processes-in-alzheimer-s-disease-w89fzzlzvv.pdf

Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers.

Distribution of the messenger RNA for the extracellularly regulated kinases 1, 2 and 3 in rat brain: effects of excitotoxic hippocampal lesions

Background: Amyloid-beta protein (Aβ) plays a key role in Alzheimer disease (AD) and is also implicated in cerebral small vessel disease. Serum total homocysteine (tHcy) is a risk factor for small vessel disease and cognitive impairment and correlates with plasma Aβ levels. To determine whether this association results from a common pathophysiologic mechanism, we investigated whether vitamin supplementation–induced reduction of tHcy influences plasma Aβ levels in the Vitamin Intervention in Stroke Prevention (VISP) study. Methods: Two groups of 150 patients treated with either the high-dose or low-dose formulation of pyridoxine, cobalamin, and folic acid in a randomized, double-blind fashion were selected among the participants in the VISP study without recurrent stroke during follow-up and in the highest 10% of the distribution for baseline tHcy levels. Concentrations of plasma Aβ with 40 (Aβ40) and 42 (Aβ42) amino acids were measured at baseline and at the 2-year visit. Results: tHcy levels significantly decreased with vitamin supplementation in both groups. tHcy were strongly correlated with Aβ40 but not Aβ42 concentrations. There was no difference in the change in Aβ40, Aβ42 ( p = 0.40, p = 0.35), or the Aβ42/Aβ40 ratio over time ( p = 0.86) between treatment groups. Aβ measures were not associated with cognitive change. Conclusions: This double-blind randomized controlled trial of vitamin therapy demonstrates a strong correlation between serum tHcy and plasma Aβ40 concentrations in subjects with ischemic stroke. Treatment with high dose vitamins does not, however, influence plasma levels of Aβ, despite their effect on lowering tHcy. Our results suggest that although tHcy is associated with plasma Aβ40, they may be regulated by independent mechanisms.

Plasma Aβ, homocysteine, and cognition: The Vitamin Intervention for Stroke Prevention (VISP) trial

Neuroanatomy of Alzheimer's disease: Hierarchical vulnerability and neural system compromise

Inheritance of the apolipoprotein E epsilon 4 allele is a risk factor for Alzheimer's disease (AD). A recent report studying Japanese patients suggested that a polymorphism of a trinucleotide repeat in the 5' untranslated region of an apolipoprotein E receptor, the very-low-density lipoprotein receptor, is genetically associated with AD, with overrepresentation of the allele containing five copies of the repeat. We determined the allele frequencies of the very-low-density lipoprotein receptor in 3 white populations totaling 469 individuals. In contrast to the previous report, we found no differences in allele frequencies between case patients and control subjects. The discrepancy could be due to differences in Japanese and white populations. Nonetheless, these data weaken the likelihood that this polymorphism in the very-low-density lipoprotein receptor gene is strongly associated with AD.

Lack of association of trinucleotide repeat polymorphisms in the very‐low‐density lipoprotein receptor gene with Alzhelner's disease

Inheritance of the apolipoprotein E (apo E) epsilon 4 allele has recently been found to be associated with Alzheimer's disease. We have studied the clinical and neuropathological correlates of apolipoprotein E genotype in a large group of Alzheimer's patients. The primary influence on clinical presentation is a shift towards earlier age of onset in individuals who have the apo E epsilon 4 gene: no change in clinical course was observed. In neuropathological studies, we find that the major influence of apo E epsilon 4 is on increased A beta deposition. These results led to a model of the biological interaction between the apo E protein and Alzheimer's disease.

B. T. Hyman

Papers

Distribution of the messenger RNA for the extracellularly regulated kinases 1, 2 and 3 in rat brain: effects of excitotoxic hippocampal lesions

Plasma Aβ, homocysteine, and cognition: The Vitamin Intervention for Stroke Prevention (VISP) trial

Neuroanatomy of Alzheimer's disease: Hierarchical vulnerability and neural system compromise

Lack of association of trinucleotide repeat polymorphisms in the very‐low‐density lipoprotein receptor gene with Alzhelner's disease

Clinical and Neuropathological Correlates of Apolipoprotein E Genotype in Alzheimer's Disease ‐ Window on Molecular Epidemiologya