Specificity, sensitivity, and predictive value of apolipoprotein-E genotyping for sporadic Alzheimer's disease

Saunders, Ann M.; Hulette, Christine M.; Welsh-Bohmer, Kathleen A.; Schmechel, Donald E.; Crain, Barbara J.; Burke, James R.; Alberts, Mark; Strittmatter, Warren J.; Breitner, Jcs; Rosenberg, Carlyn K.; Scott, Sarah; Gaskell, P. C.; Pericak‐Vance, M. A.; Roses, Allen D.

doi:10.1016/s0140-6736(96)01251-2

Cited by 236 publications

(116 citation statements)

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“…The observed negative predictive value (NPV) was low (43.3%), as the majority of AD cases did not bear the at-risk allele, thus APOE genotyping cannot be used to discard a diagnosis of AD. Although these results are based on a clinical diagnosis of AD, they are concordant with those obtained in a series of 67 necropsy-confirmed sporadic AD patients (PPV: 100%; NPV: 42%) 26 .…”

Section: Discussionsupporting

confidence: 83%

APOE epsilon4 and Alzheimer's disease: positive association in a Colombian clinical series and review of the Latin-American studies

Jacquier

Arango

Villareal

et al. 2001

Arq. Neuro-Psiquiatr.

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-Objective: As the strength of the association between the APOE ε4 allele and Alzheimers disease (AD) varies across ethnic groups, we studied if there was such an association in Colombian patients. Method: We performed apolipoprotein E (APOE) genotyping in a clinical sample of 83 unrelated AD patients, predominantly late-onset (>65 yrs) including familial ( n =30) and sporadic AD cases (n= 53) diagnosed according to NINCDS-ADRDA criteria and assessed by a multi-disciplinary team. Control subjects (n = 44) had no significant cognitive impairment by medical interview and neuro-psychological testing. Results: We found a high association (OR= 5.1 95%CI 1.9 -13.6) between APOE ε4 and AD, in this series with predominantly late-onset cases with familial aggregation in 24 cases (28.9%). A significant negative association was found between ε2 and AD (OR= 0.2 95% CI 0.05-0.75). Conclusion: Further population-based surveys in Colombia are warranted to precise a possible dose effect of APOE ε4.KEY WORDS: Alzheimers disease, APOE, dementia, risk factors, ethnic groups, Colombia.Asociación positiva entre apoe ε ε ε ε ε4 y demencia de Alzheimer en una serie clinica en Bogotá (Colombia) y revision de los estudios latinoamericanos RESUMEN -Objetivo: Como la fortaleza de la asociación entre el alelo ε4 del gen APOE y la enfermedad de Alzheimer (EA) difiere entre grupos étnicos, quisimos evaluar si esta asociación existe en pacientes colombianos. Métodos: Realizamos una genotipificación para el gen de la apolipoproteina E (APOE) en una muestra clínica de 83 pacientes con EA no relacionados, de inicio predominantemente tardío (> 65 años), incluyendo casos familiares (n=30) y esporádicos (n=53) diagnosticados según los criterios del NINCDS-ADRDA y evaluados por un equipo multi-disciplinario. Los sujetos control (n= 44) no presentaban deterioro cognoscitivo de acuerdo con la entrevista médica y la evaluación neuropsicológica. Resultados: Hallamos una alta asociación (OR= 5.1; IC95% 1.9-13.6) entre APOE ε4 y EA en la serie de casos de inicio tardío y con agregación familiar en 24 sujetos (28.9%). Una asociación negativa, estadísticamente significativa, fue encontrada entre ε2 y EA (OR= 0.2; IC95% 0.05-0.75). Conclusión: En Colombia son necesarios futuros estudios con base poblacional para poder precisar la existencia o no de un efecto de dosis de APOE ε4.PALABRAS-CLAVES: enfermedad de Alzheimer, APOE, demencia, factores de riesgo, grupos étnicos, Colombia.

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Section: Discussionsupporting

confidence: 83%

APOE epsilon4 and Alzheimer's disease: positive association in a Colombian clinical series and review of the Latin-American studies

Jacquier

Arango

Villareal

et al. 2001

Arq. Neuro-Psiquiatr.

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“…Of the individuals meeting inclusion/exclusion eligibility criteria (see below), 109 agreed to undergo APOE genotype testing from blood samples, neuropsychological evaluation, and an fMRI scanning session. APOE genotype was determined using a PCR method described by Saunders et al 7,8 DNA was isolated with Gentra Systems Autopure LS for Large Sample Nucleic Acid Purification (Minneapolis, MN).…”

Section: Participants Healthy Adults Between Ages 65 and 85 Yearsmentioning

confidence: 99%

Semantic memory activation in individuals at risk for developing Alzheimer disease

Seidenberg¹,

Guidotti²,

Nielson³

et al. 2009

Neurology

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Objective: To determine whether whole-brain, event-related fMRI can distinguish healthy older adults with known Alzheimer disease (AD) risk factors (family history, APOE 4) from controls using a semantic memory task involving discrimination of famous from unfamiliar names.Methods: Sixty-nine cognitively asymptomatic adults were divided into 3 groups (n ϭ 23 each) based on AD risk: 1) no family history, no 4 allele (control [CON]); 2) family history, no 4 allele (FH); and 3) family history and 4 allele (FHϩ4). Separate hemodynamic response functions were extracted for famous and unfamiliar names using deconvolution analysis (correct trials only). Results:Cognitively intact older adults with AD risk factors (FH and FHϩ4) exhibited greater activation in recognizing famous relative to unfamiliar names than a group without risk factors (CON), especially in the bilateral posterior cingulate/precuneus, bilateral temporoparietal junction, and bilateral prefrontal cortex. The increased activation was more apparent in the FHϩ4 than in the FH group. Unlike the 2 at-risk groups, the control group demonstrated greater activation for unfamiliar than familiar names, predominately in the supplementary motor area, bilateral precentral, left inferior frontal, right insula, precuneus, and angular gyrus. These results could not be attributed to differences in demographic variables, cerebral atrophy, episodic memory performance, global cognitive functioning, activities of daily living, or depression. Conclusions:Results demonstrate that a low-effort, high-accuracy semantic memory activation task is sensitive to Alzheimer disease risk factors in a dose-related manner. This increased activation in at-risk individuals may reflect a compensatory brain response to support task performance in otherwise asymptomatic older adults. Neurology ® 2009;73:612-620 GLOSSARY AD ϭ Alzheimer disease; AFNI ϭ Analysis of Functional NeuroImages; ANOVA ϭ analysis of variance; AUC ϭ area under the curve; BA ϭ Brodmann area; BOLD ϭ blood oxygen level-dependent; CON ϭ control; DRS-2 ϭ Dementia Rating Scale 2; DSM-IV ϭ Diagnostic and Statistical Manual of Mental Disorders, 4th edition; EM ϭ episodic memory; FH ϭ family history; FOV ϭ field of view; fROI ϭ functional region of interest; HRF ϭ hemodynamic response function; MCI ϭ mild cognitive impairment; MOANS ϭ Mayo Older Americans Normative Studies; MR ϭ magnetic resonance; MTL ϭ medial temporal lobe; NS ϭ not significant; RAVLT ϭ Rey Auditory-Verbal Learning Test; SM ϭ semantic memory; SMA ϭ supplementary motor area; SPGR ϭ spoiled gradient-recalled at steady state; TE ϭ echo time; TR ϭ repetition time; VBM ϭ voxel-based morphometry.Two well-established risk factors for the late-onset, sporadic form of Alzheimer disease (AD) are the presence of one or both copies of the apolipoprotein E (APOE) 4 allele and a firstdegree family history (FH) of AD.1,2 Task-activated fMRI studies show that cognitively intact older individuals with AD risk factors (FH, APOE 4, or both) exhibit a pattern of increased n...

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“…This observation was supported by the finding that the apoE-4 allele was present in ‫%56ف‬ of the cases with late-onset familial autosomal dominant AD and 50% of the sporadic AD cases with onset between 65 and 80 years of age (107). Recent studies have shown that ‫%46ف‬ of AD cases are associated with the presence of allele e4 of apoE (108,109), suggesting that an abnormally functioning isoform of apoE (apoE-4) may be a potentiating factor in AD pathogenesis, in addition to amyloid deposition and tangle formation (110,111). However, the precise mechanisms by which abnormal functioning of apoE-4 might lead to AD are not yet fully understood.…”

Section: Apolipoprotein E Polymorphism and App Processingmentioning

confidence: 99%

Membrane dynamics, cholesterol homeostasis, and Alzheimer's disease

Chauhan

2003

Journal of Lipid Research

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Alzheimer's disease (AD) is characterized by the deposition of ␤ -amyloid (A ␤ ) plaques derived from the amyloidogenic processing; of a transmembrane protein called ␤ -amyloid precursor protein (APP). In addition to the known genetic/sporadic factors that promote the formation of A ␤ , the composition and structural dynamics of the membrane are also thought to play a significant role in the amyloidogenic processing of APP that promotes seeding of A ␤ . This minireview reinforces the roles played by membrane dynamics, membrane microdomains, and cholesterol homeostasis in relation to amyloidogenesis, and reviews current strategies of lowering cholesterol in treating AD. -N STRUCTURE OF CELL MEMBRANEBiological membranes play a critical role in carrying out almost all physiological functions of the cell. The molecular organization of the cell membrane forms an infrastructural basis for all specialized function(s) carried out by the cell membrane. Many model membranes of varying molecular organization have been hypothesized and proposed to justify membrane functions (1-4). Among these, a dynamic fluid mosaic model (5) that evolved after several hypothetical modifications (6-8) has become a widely accepted model applicable to most biological membranes. Fluid mosaic model of cell membraneAccording to this classic model, membrane is composed of a bulk of phospholipid organized as a bilayer, with globular integral proteins embedded within the phospholipid texture. Phospholipids are arranged with their ionic and polar head groups in direct contact with the aqueous phase at the exterior and interior surfaces of the bilayer ( Fig. 1 , black gradient-filled circles), thereby maximizing hydrophilic interactions at the aqueous surfaces, while the nonpolar saturated fatty acid chains interdigitate within the interior of the membrane bilayer, forming a matrix (5). Voids and spaces between these chain aggregates are filled with lipids, of which cholesterol constitutes a major component (9, 10). The lipid matrix of the model membrane exists in three different phases, i.e., gel, liquid-ordered, and liquid-disordered states, in order of increasing fluidity (11). In the gel state, lipids are semifrozen; in the liquid-ordered state, lipids are viscous; and in the liquid-disordered state, lipids exist as fluids. This liquid-disordered fluid phase is essential for protein functions (12). The liquid-disordered fluid phase can be transformed to the liquid-ordered or gel state by tight packing of phospholipids and hydrocarbon chains with cholesterol intercalations in order of increasing rigidity (9). Thus, the amount of cholesterol present in the membrane determines the fluid/rigid state of the membrane.Integral membrane proteins [membrane anchor proteins, i.e., glycophosphatidylinositol (GPI), Src -family proteins, receptor ligands, signaling molecules, transmembrane proteins] are embedded within the phospholipid bilayer with their ionic and highly polar groups protruding to the exterior surface, and nonpolar groups largely bur...

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Specificity, sensitivity, and predictive value of apolipoprotein-E genotyping for sporadic Alzheimer's disease

Cited by 236 publications

References 31 publications

APOE epsilon4 and Alzheimer's disease: positive association in a Colombian clinical series and review of the Latin-American studies

APOE epsilon4 and Alzheimer's disease: positive association in a Colombian clinical series and review of the Latin-American studies

Semantic memory activation in individuals at risk for developing Alzheimer disease

Membrane dynamics, cholesterol homeostasis, and Alzheimer's disease

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