Jon Snaedal

Variant of TREM2 Associated with the Risk of Alzheimer's Disease

BACKGROUND Sequence variants, including the ε4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimers disease. Few rare variants affecting the risk of late-onset Alzheimers disease have been found. METHODS We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. We imputed these variants into the genomes of patients with Alzheimers disease and control participants and then tested for an association with Alzheimers disease. We performed replication tests using case-control series from the United States, Norway, The Netherlands, and Germany. We also tested for a genetic association with cognitive function in a population of unaffected elderly persons. RESULTS A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimers disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P=3.42×10(-10)). The mutation had a frequency of 0.46% in controls 85 years of age or older. We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P=2.1×10(-12) in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimers disease had poorer cognitive function than noncarriers (P=0.003). CONCLUSIONS Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimers disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimers disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.).

A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline

The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer’s disease. The age-specific prevalence of Alzheimer’s disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-β precursor protein (APP) gene with a significant effect on the risk of Alzheimer’s disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer’s disease and cognitive decline in the elderly without Alzheimer’s disease. This substitution is adjacent to the aspartyl protease β-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer’s disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer’s disease, the two may be mediated through the same or similar mechanisms.

Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease.

We conducted a search for rare, functional variants altering susceptibility to Alzheimers disease that exploited knowledge of common variants associated with the same disease. We found that loss-of-function variants in ABCA7 confer risk of Alzheimers disease in Icelanders (odds ratio (OR) = 2.12, P = 2.2 × 10−13) and discovered that the association replicated in study groups from Europe and the United States (combined OR = 2.03, P = 6.8 × 10−15).

The Effect of Midlife Physical Activity on Cognitive Function Among Older Adults: AGES—Reykjavik Study

BACKGROUND There are few studies on the long-term associations of physical activity (PA) to cognition. Here, we examine the association of midlife PA to late-life cognitive function and dementia. METHODS The sample consisted of a population-based cohort of men and women (born in 1907-1935) participating in the Age Gene/Environment Susceptibility-Reykjavik Study. The interval between the midlife ascertainment of PA and late-life cognitive function was 26 years. Composite scores of speed of processing, memory, and executive function were assessed with a battery of neuropsychological tests, and dementia was diagnosed according to international guidelines. There were 4,761 nondemented participants and 184 (3.7%) with a diagnosis of dementia, with complete data for the analysis. RESULTS Among the participants, no midlife PA was reported by 68.8%, ≤ 5 hours PA by 26.5%, and >5 hours PA by 4.5%. Excluding participants with dementia compared with the no PA group, both PA groups had significantly faster speed of processing (≤ 5 hours, β = .22; >5 hours, β = .32, p trend < .0001), better memory (≤ 5 hours, β = .15; >5 hours, β = .18, p trend < .0001), and executive function (≤ 5 hours, β = .09; >5 hours, β = .18, p trend< .0001), after controlling for demographic and cardiovascular factors. The ≤ 5 hours PA group was significantly less likely to have dementia in late life (odds ratio: 0.6, 95% confidence interval: 0.40-0.88) after adjusting for confounders. CONCLUSION Midlife PA may contribute to maintenance of cognitive function and may reduce or delay the risk of late-life dementia.

Genetic overlap between Alzheimer's Disease and Parkinson's Disease at the MAPT locus

We investigated the genetic overlap between Alzheimer’s disease (AD) and Parkinson’s disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10−7). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer’s neurodegeneration.

Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease

Background— Epidemiological findings suggest a relationship between Alzheimer disease (AD), inflammation, and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis. Methods and Results— Using summary statistics (P values and odds ratios) from genome-wide association studies of >200 000 individuals, we investigated overlap in single-nucleotide polymorphisms associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides, and high- and low-density lipoprotein levels. We found up to 50-fold enrichment of AD single-nucleotide polymorphisms for different levels of association with C-reactive protein, low-density lipoprotein, high-density lipoprotein, and triglyceride single-nucleotide polymorphisms using a false discovery rate threshold <0.05. By conditioning on polymorphisms associated with the 4 phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across 4 independent AD cohorts (total: n=29 054 AD cases and 114 824 healthy controls) and discovered 2 genome-wide significant variants on chromosome 4 (rs13113697; closest gene, HS3ST1; odds ratio=1.07; 95% confidence interval=1.05–1.11; P=2.86×10−8) and chromosome 10 (rs7920721; closest gene, ECHDC3; odds ratio=1.07; 95% confidence interval=1.04–1.11; P=3.38×10−8). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains. Conclusions— We demonstrate genetic overlap between AD, C-reactive protein, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci, including 2 genome-wide significant variants conferring increased risk for AD.

Ceruloplasmin and superoxide dismutase (SOD1) in Parkinson's disease: a follow-up study.

In this follow-up study concentration, oxidative activity and specific oxidative activity of ceruloplasmin (CP) in serum and the activity of superoxide dismutase (SOD1) in erythrocytes were reexamined in 28 of originally 40 patients with Parkinsons disease (PD), and their age- and gender-matched controls. The mean CP and SOD1 parameters were significantly lower in the patients than in the controls. SOD1 activity and age of the patients were inversely correlated. The patients were divided into two subgroups based on their H&Y score i.e. groups II and III (12 patients) versus groups IV and V (16 patients). No significant difference was found in the CP or SOD1 parameters between the subgroups. Patients were also divided into two subgroups based on treatment with levodopa and decarboxylase blocker alone (12 patients) or given additionally a dopamine agonist (15 patients). No significant difference in the parameters was found between these subgroups in relation to intake of dopamine agonists. Results of this study are in agreement with results of the former study 5 years earlier. There is considerable overlap in individual values between patients and controls of the parameters studied. Thus CP and SOD1 have no obvious value for diagnosis or clinical evaluation of PD.

Diagnostic Accuracy of Statistical Pattern Recognition of Electroencephalogram Registration in Evaluation of Cognitive Impairment and Dementia

Background: There is still a need for simple, noninvasive, and inexpensive methods to diagnose the causes of cognitive impairment and dementia. In this study, contemporary statistical methods were used to classify the clinical cases of cognitive impairment based on electroencephalograms (EEG). Methods: An EEG database was established from seven different groups of subjects with cognitive impairment and dementia as well as healthy controls. A classifier was created for each possible pair of groups using statistical pattern recognition (SPR). Results: A good-to-excellent separation was found when differentiating cases of degenerative disorders from controls, vascular disorders, and depression but this was less so when the likelihood of comorbidity was high. Conclusions: Using EEG with SPR seems to be a reliable method for diagnosing the causes of cognitive impairment and dementia, but comorbidity must betaken into account.

Ceruloplasmin and iron in Alzheimer's disease and Parkinson's disease: a synopsis of recent studies.

Ceruloplasmin (Cp) concentration and oxidative activity in serum are lowered in Parkinson’s disease (PD). In most PD patients, iron increases in the substantia nigra in the midbrain. In PD, the low Cp concentration and activity in serum and the high iron amounts in the substantia nigra appears to be correlated. An hereditary background is common in PD and variations in the Cp gene that have been found in PD are associated with high iron levels in the substantia nigra. Variations in Cp synthesis and in the incorporation of copper into the Cp molecule are essential features of PD. In Alzheimer’s disease (AD), the Cp activity in serum is lowered but not the concentration, except in the advanced stages of the disease. Generally, iron is not increased in the AD brain. In the AD brain, iron accumulates in neuritic plaques and in neurofibrillary tangles. There is also increased risk of iron-mediated tissue damage, which may possibly be counteracted by Cp. At the same time, the AD brain is short in copper, which presumably results in the deficient activity of many copper enzymes in the brain, in addition to Cp. Lowered Cp activity in serum most likely stems from lessened incorporation of copper in the Cp molecule and similar incorporation defects might also apply to other copper enzymes in AD.

Retinal Oximetry Imaging in Alzheimer's Disease

BACKGROUND Structural and physiological abnormalities have been reported in the retina in Alzheimers disease (AD). Retinal oximetry detects changes in retinal oxygen metabolism in many eye diseases, where structural changes are seen. OBJECTIVE To compare oxygen saturation in retinal blood vessels in patients with AD and a healthy cohort. METHODS Oxygen saturation of hemoglobin was measured in retinal blood vessels, using imaging with spectrophotometric noninvasive retinal oximeter. 18 individuals with mild to moderate dementia of the Alzheimer-type (stage 3-5 according to the Global Deterioration Scale) and 18 healthy subjects underwent retinal oximetry in a case control study. RESULTS Retinal oxygen saturation in arterioles and venules in patients with moderate AD was significantly elevated compared to healthy individuals. Retinal arterioles have 94.2 ± 5.4% oxygen saturation in moderate AD compared with 90.5 ± 3.1% in healthy subjects (mean ± SD, n = 10, p = 0.028). Retinal venules were 51.9 ± 6.0% saturated in moderate AD compared with 49.7 ± 7.0% in healthy subjects (mean ± SD, n = 10, p = 0.02). CONCLUSION This is the first study of retinal oxygen metabolism in any central nervous system disease. It discovers abnormalities in retinal oxygen metabolism in AD. The findings are similar to those seen in age-related macular degeneration and diabetic retinopathy. Noninvasive retinal oximetry may offer new insights into pathophysiology of AD. Further studies are needed to confirm and expand these findings.