Ingun Ulstein

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.).

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).

A one-year randomized controlled psychosocial intervention study among family carers of dementia patients--effects on patients and carers.

Objective: To test the effect of a short-term psychosocial intervention programme for family carers of patients with dementia and identify characteristics of carers and patients that responded positively. Methods: The study was a multi-centre randomized controlled trial. Carers of 180 patients suffering from dementia recruited at 7 memory clinics at geriatric or psychiatric departments participated in the study. Carers of the intervention group were educated about dementia and in 6 group meetings taught how to use structured problem-solving. The control group received treatment as usual. The effect on patients was measured with the Neuropsychiatric Inventory and on carers with the Relatives’ Stress Scale (RSS). Results: The intention-to-treat efficacy analysis included 171 carer/patient dyads. The intervention did not have any effect on the primary outcome variables. The burden measured by the RSS increased in both groups; however, more carers of the control group converted from a low-burden group to a medium- or high-burden group after 4.5 months. In a subgroup analysis we found a statistically significant difference in the Neuropsychiatric Inventory score in favour of the intervention group among female patients. Conclusion: The predominately negative result of this study emphasizes the need of individually tailored interventions for carers and the use of narrow inclusion criteria when performing group-based interventions, such as the extent of burden as well as gender and kinship.

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.

The Quality of Life of People with Dementia and Their Family Carers

Background: We aimed to identify factors associated with the quality of life (QoL) of ‘persons with dementia’ (PWDs) and their family carers. Method: Two-hundred and thirty dyads of PWDs and their family carers were included. The PWDs were assessed with the Neuropsychiatric Inventory (NPI-Q), two Activities of Daily Living (ADL) scales, the Cornell Scale and the QoL-Alzheimer’s Disease scale (QoL-AD; self- and proxy-reported scores). The carers were assessed with the QoL-AD and the Geriatric Depression Scale. Results: Factors associated with self-reported QoL were depression (β = –0.26, p < 0.001) and impaired ADL (β = –0.26, p < 0.001) and with proxy-rated QoL were NPI (β = –0.18, p = 0.02), depression (β = –0.32, p < 0.001) and impaired ADL (β = –0.43, p < 0.001). Factors associated with QoL in carers living together with the PWDs were depression (β = –0.56, p < 0.001) and having a hobby (β = 0.19, p = 0.01), whereas depression was associated with QoL in those who lived separately from the PWD (β = –0.60, p < 0.001). Conclusion: Depression and impaired ADL were associated with the self- and proxy-rated QoL of the PWDs, whereas depression in the carers negatively affected their QoL.

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.

The Memory Clinic - outpatient assessment when dementia is suspected

The patients who are assessed at Oslo University Hospitals Memory Clinic are young--half of them are under 65 years of age. Most are suffering from mild cognitive impairment or dementia at a very early phase while others come to get a second opinion. The assessment takes 2 - 3 hours and is conducted by a doctor and a nurse. It includes a clinical investigation, cognitive testing, an MRI scan with measurement of the medial temporal lobes, a lumbar puncture and single-photon-emission tomography (SPECT of the brain).

Caregiver burden in family carers of people with dementia with Lewy bodies and Alzheimer's disease

To characterise the differences in caregiver distress between carers of people diagnosed with dementia with Lewy bodies (DLB) and people with Alzheimers disease (AD), with a view to differentiating and improving support for caregivers.

The effect of coping on the burden in family carers of persons with dementia

Objectives: This study explores the association between coping, measured by the extent of locus of control, and the burden of care on family carers of persons with dementia (PWD). Method: Two hundred thirty PWD living at home and their family carers were recruited from 20 Norwegian municipalities. The carers’ burden was assessed by the Relatives’ Stress Scale (RSS) and coping by the Locus of Control Behaviour Scale. The PWD were assessed by the Neuropsychiatric Inventory (NPI-Q), the Physical Self-Maintenance Scale (PSMS), the Instrumental Activities of Daily Living (IADL) scale, and the Mini Mental Status Examination (MMSE). Results: Locus of control (LoC) was found to be the most important factor associated with the burden on carers of PWD, even when we had controlled for the PWD variables, such as the NPI-Q score. The LoC and the carers use of hours per day to assist the PWD were the only two variables the carers found that affected the extent of the burden. The NPI-Q was the most important variable in the PWD that affected the burden on the carers. Conclusion: Carers who believe that what happens to them is the consequence of their own actions are likely to be less burdened than carers not expecting to have control. This finding gives a possibility to identify carers with a high risk of burden.

Patterns of neuropsychiatric sub-syndromes in Brazilian and Norwegian patients with dementia

BACKGROUND Neuropsychiatric symptoms (NPS) affect the majority of patients who have dementia. Neuropsychiatric sub-syndromes with symptoms that occur together and have common neurobiological correlates have been identified. There are scarce data regarding the comparison of the pattern of the neuropsychiatric sub-syndromes in distinct ethnical and cultural populations. We aim at comparing the pattern of the NPS, and the factor analysis of the Neuropsychiatric Inventory (NPI-10) in two samples of outpatients with dementia living in Brazil and Norway. METHODS This is a cross-sectional study. The sample consists of 168 Brazilian and 155 Norwegian demented patients from psychogeriatric facilities and community-based educational programs. Brazilian patients were diagnosed with Alzheimers disease (63.7%), vascular dementia (15.5%), or mixed dementia (20.8%), whereas the diagnoses of Norwegian patients were Alzheimers disease (97.4%) and mixed dementia (2.6%). Principal component analysis with the Varimax rotation was used for factor analysis of the NPI-10. RESULTS Apathy (80.4 %), agitation/aggression (45.8%), and aberrant motor behavior (45.8%) were the most common symptoms in the Brazilian sample. Apathy (72.3%), dysphoria (61.9%), and anxiety (52.3%) were the most frequent symptoms in the Norwegian sample. Factor analysis of the NPI-10 revealed three syndromes for the Brazilian (Psychosis, Mood, Psychomotor) and Norwegian (Psychosis, Mood, Frontal) groups. CONCLUSIONS The frequency of individual NPS may differ among distinct populations. However, Psychosis and Depression are common sub-syndromes in diverse ethnical and cultural patients with dementia. Our findings support the syndromic approach for the clinical assessment of the patients with dementia.