The genetics of Alzheimer’s disease

Alzheimer’s disease (AD) is a genetically complex disorder. Mutations in the amyloid precursor protein and presenilin 1 (PS1) genes are fully penetrant and cause early-onset AD. Mutations in presenilin 2, a PS1 homologue, cause partially penetrant autosomal dominant AD with onset age beginning at 40 years and extending past 75 years. A fourth gene, apolipoprotein E (ApoE) is a riskfactor for late-onset AD. Over 40 genes have been tested as AD candidate genes, yet none has been clearly established as an AD risk factor. Linkage studies have implicated a number of chromosome regions as possible sites for late-onset AD loci with the strongest evidence being for chromosome 12. Candidate genes in this regioninclude α2-macroglobulin (A2M) and low-density lipoprotein receptor-related gene (LRP), although neither has been clearly established as an AD gene. Identification of additional late-onset genes will require larger samples, more sophisticated analysis methods, and large-scale positional cloning efforts.     

The genetics and neuropathology of Alzheimer’s disease

Here we review the genetic causes and risks for Alzheimer’s disease (AD). Early work identified mutations in three genes that cause AD: APP, PSEN1 and PSEN2. Although mutations in these genes are rare causes of AD, their discovery had a major impact on our understanding of molecular mechanisms of AD. Early work also revealed the ε4 allele of the APOE as a strong risk factor for AD. Subsequently, SORL1 also was identified as an AD risk gene. More recently, advances in our knowledge of the human genome, made possible by technological advances and methods to analyze genomic data, permit systematic identification of genes that contribute to AD risk. This work, so far accomplished through single nucleotide polymorphism arrays, has revealed nine new genes implicated in AD risk (ABCA7, BIN1, CD33, CD2AP, CLU, CR1, EPHA1, MS4A4E/MS4A6A, and PICALM). We review the relationship between these mutations and genetic variants and the neuropathologic features of AD and related disorders. Together, these discoveries point toward a new era in neurodegenerative disease research that impacts not only AD but also related illnesses that produce cognitive and behavioral deficits.     

The concept of FDG-PET endophenotype in Alzheimer’s disease

Often viewed as a potential tool for preclinical diagnosis in early asymptomatic stages of Alzheimer’s disease (AD), the term “endophenotype” has acquired a recent popularity in the field. In this review, we analyze the construct of endophenotype—originally designed to discover genes, and examine the literature on potential endophenotypes for the late-onset form of AD (LOAD). We focus on the [18F]-fluoro-2-deoxyglucose (FDG) PET technique, which shows a characteristic pattern of hypometabolism in AD-related regions in asymptomatic carriers of the ApoE E4 allele and in children of AD mothers. We discuss the pathophysiological significance and the positive predictive accuracy of an FDG-endophenotype for LOAD in asymptomatic subjects, and discuss several applications of this endophenotype in the identification of both promoting and protective factors. Finally, we suggest that the term “endophenotype” should be reserved to the study of risk factors, and not to the preclinical diagnosis of LOAD.     

The significance of neuroinflammation in understanding Alzheimer’s disease

Summary. The interest of scientists in the involvement of inflammation-related mechanisms in the pathogenesis of Alzheimer’s disease (AD) goes back to the work of one of the pioneers of the study of this disease. About hundred years ago Oskar Fischer stated that the crucial step in the plaque formation is the extracellular deposition of a foreign substance that provokes an inflammatory reaction followed by a regenerative response of the surrounding nerve fibers. Eighty years later immunohistochemical studies revealed that amyloid plaques are indeed co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. These findings have led to the view that the amyloid plaque is the nidus of a non-immune mediated chronic inflammatory response locally induced by fibrillar Aβ deposits. Recent neuropathological studies show a close relationship between fibrillar Aβ deposits, inflammation and neuroregeneration in relatively early stages of AD pathology preceding late AD stages characterized by extensive tau-related neurofibrillary changes. In the present work we will review the role of inflammation in the early stage of AD pathology and particularly the role of inflammation in Aβ metabolism and deposition. We also discuss the possibilities of inflammation-based therapeutic strategies in AD.     

Glyceraldehyde-derived advanced glycation end products in Alzheimer’s disease

The Maillard reaction that leads to the formation of advanced glycation end products (AGE) is considered to play an important role in the pathogenesis of Alzheimers disease (AD). Until now AGE derived from glucose (glucose-AGE) have been mainly investigated, so we established new AGE species derived from -hydroxyaldehydes and dicarbonyl compounds. We have found that AGE derived from glyceraldehyde (glycer-AGE) and glycolaldehyde (glycol-AGE) showed strong neurotoxicity for primary cultured rat cortical neurons in vitro. In this study, we immunohistochemically examined the localization of glycer-AGE and glycol-AGE in the brains of AD patients and elderly controls. Most of the neurons in AD or control brains did not show any immunoreaction with glycol-AGE. In AD brains, glycer-AGE was mainly present in the cytosol of neuron in the hippocampus and para-hippocampal gyrus, but not in senile plaques and astrocytes. The pattern of immunopositivity was uniform and powdery, not dot-like. The distribution of glycer-AGE differed from that of glucose-AGE, which was detected at both intracellular and extracellular sites. This suggests that glycer-AGE has a pathological role different from glucose-AGE in AD. In the central nervous system, glyceraldehyde is generated via the glycolytic pathway from glyceraldehyde-3-phosphate by glyceraldehyde-3-phosphate dehydrogenase (GAPDH). We hypothesize that perikaryal glycer-AGE immunopositivity of neurons reflects an increase of cytoplasmic glycer-AGE along with the decline of GAPDH activity.     

Iron: a pathological mediator of Alzheimer disease?

Brains from patients with Alzheimer disease (AD) show a disruption in the metabolism of iron, such that there is an accumulation of iron in senile plaques, and an altered distribution of iron transport and storage proteins. One of the earliest events in AD is the generation of oxidative stress, which may be related to the generation of free radicals by the excess iron that is observed in the disease. Iron has also been shown to mediate the in vitro toxicity of amyloid-beta peptide, and the presence of iron in most in vitro systems could underlie the toxicity that is normally attributed to amyloid-beta in these studies. In contrast, several recent studies have suggested that amyloid-beta may decrease oxidative stress and decrease the toxicity of iron. Continued examination of the complex interactions that occur between iron and amyloid-beta may assist in the elucidation of the mechanisms that underlie the neurodegeneration that leads to dementia in AD.     

The propagation mechanisms of extracellular tau in Alzheimer’s disease

Journal of Neurology - Tubulin-associated unit (tau) is an important microtubule-associated protein. The abnormal intracellular aggregation of tau has been strongly associated...     

Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study

BACKGROUND: Prior reports suggest reduced occurrence of dementia and Alzheimer disease (AD) in statin users, but, to our knowledge, no prospective studies relate statin use and dementia incidence. OBJECTIVE: To examine the association of statin use with both prevalence and incidence of dementia and AD. DESIGN: Cross-sectional studies of prevalence and incidence and a prospective study of incidence of dementia and AD among 5092 elderly residents (aged 65 years or older) of a single county. Participants were assessed at home in 1995-1997 and again in 1998-2000. A detailed visual inventory of medicines, including statins and other lipid-lowering agents, was collected at both assessments. MAIN OUTCOME MEASURES: Diagnosis of dementia and of AD. RESULTS: From 4895 participants with data sufficient to determine cognitive status, we identified 355 cases of prevalent dementia (200 with AD) at initial assessment. Statin use was inversely associated with prevalence of dementia (adjusted odds ratio, 0.44; 95% confidence interval, 0.17-0.94). Three years later, we identified 185 cases of incident dementia (104 with AD) among 3308 survivors at risk. Statin use at baseline did not predict incidence of dementia or AD (adjusted hazard ratio for dementia, 1.19; 95% confidence interval, 0.53-2.34; adjusted hazard ratio for AD, 1.19; 95% confidence interval, 0.35-2.96), nor did statin use at follow-up (adjusted odds ratio for dementia, 1.04; 95% confidence interval, 0.56-1.81; adjusted odds ratio for AD, 0.85; 95% confidence interval, 0.32-1.88). CONCLUSIONS: Although statin use might be less frequent in those with prevalent dementia, we found no association between statin use and subsequent onset of dementia or AD. Further research is warranted before costly dementia prevention trials with statins are undertaken.