Replication of genetic association findings in independent studies represents an important validation tool in the search for susceptibility genes for complex diseases such as Alzheimer's disease ...(AD). In a well-characterized memory-clinic based study comprising 1078 unrelated AD patients and 652 control individuals, we set out to replicate previously reported genome-wide association of four novel risk SNPs with AD and onset age, with first stage p-values ranging from 0.001 to 0.000004. We obtained evidence for association between rs179943, an intronic SNP in ATXN1 at 6p22.3, and affection status (OR = 0.63 (95% CI = 0.44-0.90; nominal p = 0.01)). Overall, our data provided independent support for association of at least one chromosomal locus with AD and warranted a more in-depth investigation of these regions for possible underlying functional variants.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Frontotemporal lobar degeneration (FTLD) is a highly familial neurodegenerative disease. It has been claimed that homozygosity of the SNP rs5848 located in the 3'UTR of progranulin increases risk for ...FTLD. We have attempted to replicate the association of rs5848 in three independent FTLD cohorts. No association of rs5848 with FTLD was observed in any individual cohort nor was any observed when the data was combined. These data argue that rs5848 is not a risk factor for FTLD.
A link between Tau phosphorylation and aggregation has been shown in different models for Alzheimer disease, including yeast. We used human Tau purified from yeast models to generate new monoclonal ...antibodies, of which three were further characterized. The first antibody, ADx201, binds the Tau proline-rich region independently of the phosphorylation status, whereas the second, ADx215, detects an epitope formed by the Tau N terminus when Tau is not phosphorylated at Tyr18. For the third antibody, ADx210, the binding site could not be determined because its epitope is probably conformational. All three antibodies stained tangle-like structures in different brain sections of THY-Tau22 transgenic mice and Alzheimer patients, and ADx201 and ADx210 also detected neuritic plaques in the cortex of the patient brains. In hippocampal homogenates from THY-Tau22 mice and cortex homogenates obtained from Alzheimer patients, ADx215 consistently stained specific low order Tau oligomers in diseased brain, which in size correspond to Tau dimers. ADx201 and ADx210 additionally reacted to higher order Tau oligomers and presumed prefibrillar structures in the patient samples. Our data further suggest that formation of the low order Tau oligomers marks an early disease stage that is initiated by Tau phosphorylation at N-terminal sites. Formation of higher order oligomers appears to require additional phosphorylation in the C terminus of Tau. When used to assess Tau levels in human cerebrospinal fluid, the antibodies permitted us to discriminate patients with Alzheimer disease or other dementia like vascular dementia, indicative that these antibodies hold promising diagnostic potential.
Background: Oligomers of protein Tau are associated with neurodegenerative diseases.
Results: New antibodies were generated and validated that recognize different degrees of oligomerization of protein Tau.
Conclusion: Low order and higher order oligomers differ in C-terminal Tau phosphorylation and reflect consecutive stages in disease progression.
Significance: Antibodies recognizing Tau oligomers provide insight into disease etiology and are promising diagnostic tools.
Abstract
Introduction
The ability to identify individuals at increased genetic risk for Alzheimer's disease (AD) may streamline biomarker and drug trials and aid clinical and personal decision ...making.
Methods
We evaluated the discriminative ability of a genetic risk score (GRS) covering 22 published genetic risk loci for AD in 1162 Flanders‐Belgian AD patients and 1019 controls and assessed correlations with family history, onset age, and cerebrospinal fluid (CSF) biomarkers (Aβ
1–42
, T‐Tau, P‐Tau
181P
).
Results
A GRS including all single nucleotide polymorphisms (SNPs) and age‐specific
APOE ε4
weights reached area under the curve (AUC) 0.70, which increased to AUC 0.78 for patients with familial predisposition. Risk of AD increased with GRS (odds ratio, 2.32 (95% confidence interval 2.08–2.58 per unit;
P
< 1.0e
−15
). Onset age and CSF Aβ
1–42
decreased with increasing GRS (
P
onset_age
= 9.0e
−11
;
P
Aβ
= 8.9e
−7
).
Discussion
The discriminative ability of this 22‐SNP GRS is still limited, but these data illustrate that incorporation of age‐specific weights improves discriminative ability. GRS‐phenotype correlations highlight the feasibility of identifying individuals at highest susceptibility.
This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) ...amyloid-β1-42, tau, and phosphorylated tau in the diagnostic evaluation of patients with dementia. The recommendations were developed by a multidisciplinary working group based on the available evidence and consensus from focused discussions for (i) identification of Alzheimer's disease (AD) as the cause of dementia, (ii) prediction of rate of decline, (iii) cost-effectiveness, and (iv) interpretation of results. The working group found sufficient evidence to support a recommendation to use CSF AD biomarkers as a supplement to clinical evaluation, particularly in uncertain and atypical cases, to identify or exclude AD as the cause of dementia. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Operational recommendations for the interpretation of ambiguous CSF biomarker results were also provided.
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