Dataset Information

Alzheimer risk loci and associated neuropathology in a population-based study (Vantaa 85+).

ABSTRACT: Objective:To test the association of distinct neuropathologic features of Alzheimer disease (AD) with risk loci identified in genome-wide association studies. Methods:Vantaa 85+ is a population-based study that includes 601 participants aged ?85 years, of which 256 were neuropathologically examined. We analyzed 29 AD risk loci in addition to APOE ?4, which was studied separately and used as a covariate. Genotyping was performed using a single nucleotide polymorphism (SNP) array (341 variants) and imputation (6,038 variants). Participants with Consortium to Establish a Registry for Alzheimer Disease (CERAD) (neuritic A? plaques) scores 0 (n = 65) vs score M + F (n = 171) and Braak (neurofibrillary tangle pathology) stages 0-II (n = 74) vs stages IV-VI (n = 119), and with capillary A? (CapA?, n = 77) vs without (n = 179) were compared. Cerebral amyloid angiopathy (CAA) percentage was analyzed as a continuous variable. Results:Altogether, 24 of the 29 loci were associated (at p < 0.05) with one or more AD-related neuropathologic features in either SNP array or imputation data. Fifteen loci associated with CERAD score, smallest p = 0.0002122, odds ratio (OR) 2.67 (1.58-4.49) at MEF2C locus. Fifteen loci associated with Braak stage, smallest p = 0.004372, OR 0.31 (0.14-0.69) at GAB2 locus. Twenty loci associated with CAA, smallest p = 7.17E-07, ? 14.4 (8.88-20) at CR1 locus. Fifteen loci associated with CapA? smallest p = 0.002594, OR 0.54 (0.37-0.81) at HLA-DRB1 locus. Certain loci associated with specific neuropathologic features. CASS4, CLU, and ZCWPW1 associated only with CAA, while TREM2 and HLA-DRB5 associated only with CapA?. Conclusions:AD risk loci differ in their association with neuropathologic features, and we show for the first time distinct risk loci for CAA and CapA?.

SUBMITTER: Makela M

PROVIDER: S-EPMC5773846 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Alzheimer risk loci and associated neuropathology in a population-based study (Vantaa 85+).

Mäkelä Mira M Kaivola Karri K Valori Miko M Paetau Anders A Polvikoski Tuomo T Singleton Andrew B AB Traynor Bryan J BJ Stone David J DJ Peuralinna Terhi T Tienari Pentti J PJ Tanskanen Maarit M Myllykangas Liisa L

Neurology. Genetics 20180118 1

<h4>Objective</h4>To test the association of distinct neuropathologic features of Alzheimer disease (AD) with risk loci identified in genome-wide association studies.<h4>Methods</h4>Vantaa 85+ is a population-based study that includes 601 participants aged ≥85 years, of which 256 were neuropathologically examined. We analyzed 29 AD risk loci in addition to <i>APOE</i> ε4, which was studied separately and used as a covariate. Genotyping was performed using a single nucleotide polymorphism (SNP) a ...[more]

PMID: 29379882

Similar Datasets

Project description:BackgroundStudies have reported a protective relation to cognitive decline with long-term intake of total and individual dietary carotenoids. However, the underlying mechanisms have not yet been clearly established in humans.ObjectivesTo evaluate the prospective association between intakes of total and individual carotenoids and risk of incident Alzheimer dementia (AD) and explore the underlying neuropathological basis.MethodsAmong 927 participants from the Rush Memory and Aging Project who were free from AD at baseline and were followed up for a mean of 7 y, we estimated HRs for AD using Cox proportional hazards models by intakes of energy-adjusted carotenoids. Brain AD neuropathology was assessed in postmortem brain autopsies among 508 deceased participants. We used linear regression to assess the association of carotenoid intake with AD-related neuropathology.ResultsHigher intake of total carotenoids was associated with substantially lower hazard of AD after controlling for age, sex, education, ApoE-ε4, participation in cognitively stimulating activities, and physical activity level. Comparing the top and bottom quintiles (median intake: 24.8 compared with 6.7 mg/d) of total carotenoids, the multivariate HR (95% CI) was 0.52 (0.33, 0.81), P-trend < 0.01. A similar association was observed for lutein-zeaxanthin, a weaker linear inverse association was observed for β-carotene, and a marginally significant linear inverse association was found for β-cryptoxanthin. Among the deceased participants, consumers of higher total carotenoids (top compared with bottom tertile, 18.2 compared with 8.2 mg/d) had less global AD pathology (b: -0.10; SE = 0.04; P-trend = 0.01). For individual carotenoids, lutein-zeaxanthin and lycopene were inversely associated with brain global pathology, whereas lutein-zeaxanthin showed additional inverse associations with AD diagnostic score, neuritic plaque severity, and neurofibrillary tangle density and severity.ConclusionsOur findings support a beneficial role of total carotenoid consumption, in particular lutein/zeaxanthin, on AD incidence that may be related to the inhibition of brain β-amyloid deposition and fibril formation.

Project description:Animal models aim to replicate the symptoms, the lesions or the cause(s) of Alzheimer disease. Numerous mouse transgenic lines have now succeeded in partially reproducing its lesions: the extracellular deposits of Abeta peptide and the intracellular accumulation of tau protein. Mutated human APP transgenes result in the deposition of Abeta peptide, similar but not identical to the Abeta peptide of human senile plaque. Amyloid angiopathy is common. Besides the deposition of Abeta, axon dystrophy and alteration of dendrites have been observed. All of the mutations cause an increase in Abeta 42 levels, except for the Arctic mutation, which alters the Abeta sequence itself. Overexpressing wild-type APP alone (as in the murine models of human trisomy 21) causes no Abeta deposition in most mouse lines. Doubly (APP x mutated PS1) transgenic mice develop the lesions earlier. Transgenic mice in which BACE1 has been knocked out or overexpressed have been produced, as well as lines with altered expression of neprilysin, the main degrading enzyme of Abeta. The APP transgenic mice have raised new questions concerning the mechanisms of neuronal loss, the accumulation of Abeta in the cell body of the neurons, inflammation and gliosis, and the dendritic alterations. They have allowed some insight to be gained into the kinetics of the changes. The connection between the symptoms, the lesions and the increase in Abeta oligomers has been found to be difficult to unravel. Neurofibrillary tangles are only found in mouse lines that overexpress mutated tau or human tau on a murine tau -/- background. A triply transgenic model (mutated APP, PS1 and tau) recapitulates the alterations seen in AD but its physiological relevance may be discussed. A number of modulators of Abeta or of tau accumulation have been tested. A transgenic model may be analyzed at three levels at least (symptoms, lesions, cause of the disease), and a reading key is proposed to summarize this analysis.

Dataset Information

Alzheimer risk loci and associated neuropathology in a population-based study (Vantaa 85+).

Publications

Alzheimer risk loci and associated neuropathology in a population-based study (Vantaa 85+).

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets