Eloy Rodríguez-Rodríguez

Low serum VEGF levels are associated with Alzheimer's disease.

Objective –  As vascular endothelial growth factor (VEGF) determines important neurotrophic and neuroprotective actions, we postulated serum VEGF levels could be abnormally low in patients with Alzheimers disease (AD).

Age-dependent association of KIBRA genetic variation and Alzheimer's disease risk.

An association between memory performance in healthy young, middle aged an elderly subjects and variability in the KIBRA gene (rs17070145) has been recently described. We analyzed this polymorphism in 391 sporadic Alzheimers disease (AD) patients and 428 cognitively normal control subjects. The current study reveals that KIBRA (rs17070145) T allele (CT and TT genotypes) is associated with an increased risk (OR 2.89; p=0.03) for very-late-onset (after the age of 86 years) AD.

Amyloid precursor protein metabolism and inflammation markers in preclinical Alzheimer disease

Objective: To investigate CSF markers involved in amyloid precursor protein processing, neuronal damage, and neuroinflammation in the preclinical stages of Alzheimer disease (AD) and participants with suspected non-Alzheimer pathology (SNAP). Methods: We collected CSF from 266 cognitively normal volunteers participating in a cross-sectional multicenter study (the SIGNAL study) to investigate markers involved in amyloid precursor protein processing (Aβ42, sAPPβ, β-secretase activity), neuronal damage (total-tau [t-tau], phospho-tau [p-tau]), and neuroinflammation (YKL-40). We analyzed the relationship among biomarkers, clinical variables, and the APOE genotype, and compared biomarker levels across the preclinical stages of the National Institute on Aging–Alzheimers Association classification: stage 0, 1, 2, 3, and SNAP. Results: The median age in the whole cohort was 58.8 years (range 39.8–81.6). Participants in stages 2–3 and SNAP had higher levels of YKL-40 than those in stages 0 and 1. Participants with SNAP had higher levels of sAPPβ than participants in stage 0 and 1. No differences were found between stages 0, 1, and 2–3 in sAPPβ and β-secretase activity in CSF. Age correlated with t-tau, p-tau, and YKL-40. It also correlated with Aβ42, but only in APOE ε4 carriers. Aβ42 correlated positively with t-tau, sAPPβ, and YKL-40 in participants with normal Aβ42. Conclusions: Our findings suggest that inflammation in the CNS increases in normal aging and is intimately related to markers of neurodegeneration in the preclinical stages of AD and SNAP. sAPPβ and β-secretase activity are not useful diagnostic or staging markers in preclinical AD.

Assessing the role of the TREM2 p.R47H variant as a risk factor for Alzheimer's disease and frontotemporal dementia

A non-synonymous genetic rare variant, rs75932628-T (p.R47H), in the TREM2 gene has recently been reported to be a strong genetic risk factor for Alzheimers disease (AD). Also, rare recessive mutations have been associated with frontotemporal dementia (FTD). We aimed to investigate the role of p.R47H variant in AD and FTD through a multi-center study comprising 3172 AD and 682 FTD patients and 2169 healthy controls from Spain. We found that 0.6% of AD patients carried this variant compared to 0.1% of controls (odds ratio [OR] = 4.12, 95% confidence interval [CI] = 1.21-14.00, p = 0.014). A meta-analysis comprising 32,598 subjects from 4 previous studies demonstrated the large effect of the p.R47H variant in AD risk (OR = 4.11, 95% CI = 2.99-5.68, p = 5.27×10(-18)). We did not find an association between p.R47H and age of onset of AD or family history of dementia. Finally, none of the FTD patients harbored this genetic variant. These data strongly support the important role of p.R47H in AD risk, and suggest that this rare genetic variant is not related to FTD.

Detection of early Alzheimer's disease in MCI patients by the combination of MMSE and an episodic memory test.

BackgroundMild cognitive impairment (MCI) is a heterogeneous clinical entity that comprises the prodromal phase of Alzheimers disease (Pr-AD). New biomarkers are useful in detecting Pr-AD, but they are not universally available. We aimed to investigate baseline clinical and neuropsychological variables that might predict progression from MCI to AD dementia.MethodsAll patients underwent a complete clinical and neuropsychological evaluation at baseline and every 6 months during a two-year follow-up period, with 54 out of 109 MCI patients progressing to dementia (50 of them progressed to AD dementia), and 55 remaining as stable MCI (S-MCI).ResultsA combination of MMSE and California Verbal Learning Test Long Delayed Total Recall (CVLT-LDTR) constituted the best predictive model: subjects scoring above 26/30 on MMSE and 4/16 on CVLT-LDTR had a negative predictive value of 93.93% at 2 years, whereas those subjects scoring below both of these cut-off scores had a positive predictive value of 80.95%.ConclusionsPr-AD might be distinguished from S-MCI at baseline using the combination of MMSE and CVLT-LDTR. These two neuropsychological predictors are relatively brief and may be readily completed in non-specialist clinical settings.

Interaction between poly(ADP-ribose) polymerase 1 and interleukin 1A genes is associated with Alzheimer's disease risk.

Excessive release of proinflammatory cytokines by activated microglia surrounding senile plaques might contribute to the neurodegeneration associated with Alzheimer’s disease (AD). Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear protein recently implicated in the initial inflammatory response by modulating expression of inflammation-related genes, like interleukin 1 (IL-1). As PARP-1 overactivity has been shown in the AD brain, we tested the hypothesis that the PARP-1 –410 and –1672 polymorphisms would predispose people to AD due to overexpression of the PARP-1 gene, independently or in concert with the proinflammatory IL-1A –889 polymorphism. So, we performed a case-control study in 263 Spanish AD patients and 293 healthy controls. PARP-1 –410 and PARP-1 –1672 haplotypes were associated with an increased risk for AD (global haplotype association p value = 0.019), and, in addition, PARP-1 haplotypes increased the risk of AD by interaction with the IL-1A –889 allele 2.

Association of genetic variants of ABCA1 with Alzheimer's disease risk.

ABCA1 plays key roles in cholesterol transport and apolipoprotein E (APOE) metabolism in the brain. To evaluate the relationship between ABCA1 genetic variants and Alzheimers disease (AD), independently or in concert with the APOE ε4 allele, we examined three ABCA1 polymorphisms located in the coding region (R219K, I883M, and R1587K) and two ABCA1 polymorphisms in the promoter region (C−14T and C−477T) in a group of 372 Spanish AD patients and 440 controls. The ABCA1 219K, 883I, 1587R haplotype was significantly associated with AD, conferring a risk of 1.78 (P = 0.007). The ABCA1 C−14T polymorphism modified the risk of AD in an APOE ε4 allele‐dependent fashion: in APOE ε4 carriers, homozygous for the ABCA1 −14T allele had 3.7 times higher risk of developing AD (OR = 13.99) than carriers of the ABCA1 −14CC and CT genotypes (OR = 3.79). These data suggest that the development of AD might be influenced by either a qualitative change of the ABCA1 protein caused by coding region variants (219K, 883I, and 1587R), or by a quantitative change in ABCA1 expression caused by promoter region variant (−14T) in concert with the APOE ε4 allele.

Serum heme oxygenase‐1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease

Mateo I, Infante J, Sánchez‐Juan P, García‐Gorostiaga I, Rodríguez‐Rodríguez E, Vázquez‐Higuera JL, Berciano J, Combarros O. Serum heme oxygenase‐1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease.
Acta Neurol Scand: 2010: 121: 136–138.
© 2009 The Authors Journal compilation

Gene-gene interaction between heme oxygenase-1 and liver X receptor-β and Alzheimer's disease risk.

Increasing cellular cholesterol levels results in high amyloid beta (Abeta) synthesis, which is central to the pathogenesis of Alzheimers disease (AD). Heme oxygenase-1 (HO-1) stimulates oxidation of glial cholesterol to oxysterols, and increased oxysterol concentrations may protect neural tissues by activation of liver X receptor-beta (LXR-beta), which induces transcription of genes associated with reduction of cellular cholesterol concentrations and decrease of Abeta formation. Underexpression of HO-1 in concert with underexpression of LXR-beta would result in increased cholesterol accumulation, induction of Abeta production, and increased AD risk. We examined a functional polymorphism in the HO-1 promoter region (-413, rs2071746), and three LXR-beta polymorphisms in introns 2 (rs2695121), 5 (rs1052533), and 7 (rs1405655), in a group of 414 Spanish AD cases and 442 controls. Subjects carrying both the HO-1 (-413) TT genotype and the LXR-beta (intron 2) TT genotype (OR=2.63), LXR-beta (intron 5) AA genotype (OR=1.90), or LXR-beta (intron 7) TT genotype (OR=1.75) had a higher risk of developing AD than subjects without these risk genotypes. Considering synergistic effects between polymorphisms in cellular cholesterol efflux-related genes may help in determining the risk profile for AD.

Poly (ADP-ribose) polymerase-1 (PARP-1) genetic variants are protective against Parkinson's disease

Poly (ADP-ribose) polymerase-1 (PARP-1) is involved in crucial pathogenic events in Parkinsons disease (PD). We studied the effect of promoter variations of PARP-1 gene on the risk for PD in a case-control association study comprising 146 PD patients and 161 controls from Northern Spain. Three polymorphisms from the promoter region of PARP-1 gene were analyzed: -410C/T, -1672G/A, and a (CA)n microsatellite. A protective effect against PD was found for heterozygosity at (-410) (OR 0.44) and (CA)n microsatellite (OR 0.53) polymorphisms, and heterozygosity at (-1672) polymorphism delayed by 4 years on the onset age of PD. Variations in the regulatory region of PARP-1 gene might modify the risk for PD.