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Since apoE allele status is the predominant Alzheimers disease (AD) genetic risk factor, functional single nucleotide polymorphisms (SNPs) in brain apoE receptors represent excellent candidates for association with AD. Therefore, three low density lipoprotein receptor (LDLR) SNPs were evaluated by TaqMan allelic discrimination assays for association with AD and I found that certain haplotypes alter the odds of AD. A SNP within LDLR exon 12, rs688, was identified in silico as neutralizing a putative exon splicing enhancer (ESE). Since LDLR is a major apoE receptor in the brain, I hypothesized that rs688 modulates LDLR splicing in neural tissues and associates with AD. To evaluate this hypothesis, I analyzed splicing patterns in human hippocampus samples and established that this SNP was associated with significantly decreased LDLR exon 12 splicing efficiency when the minor allele T is present in vivo. Lastly, I evaluated whether rs688 associates with AD by genotyping DNA from the Religious Orders Study (ROS) series. The rs688T/T genotype was associated with increased AD odds in males, but not in females, in a dataset consisting of 1,457 men and 2,055 women drawn from three case-control series. The rs688T/T genotype was associated with increased AD odds in males (recessive model, odds ratio (OR) of 1.49, 95% confidence interval (CI) of 1.13- 1.97, uncorrected p=0.005), but not in females. In summary, these studies identify a functional apoE receptor SNP that is associated with AD in a sex-dependent fashion.

In previous studies there has been indications that multilingualism has a delaying effect of the onset of dementia and damage on cognitive abilities (Bialystok et al., 2007; De Bot & Makoni, 2005, s. 58). Cognitive abilities refers to memory, attention, language, abstract thinking and understandings among other things (Läkemedelsverket). Other studies have seen that individuals with Alzheimer's disease (Swedish abbreviation AS from here on) have difficulties with managing a conversation (Hyltenstam & Stroud 1989). This study aims to describe the topic treatment in bilingual individuals with AS and compare their different languages. The study also compares the multilingualism with monolinguals with respect to topic treatment. Through a qualitative analysis the ability to maintain and introduce topic in a conversation is researched. The study is a casestudy of four individuals with AS two of which were monolinguals with Swedish as their mother tongue and two were bilinguals with Swedish as their second language and finish as their first language. The language was examined through a semistructured interview based in discourse analysis with prepared questions as to ease the flow of the conversation. Narrative ability was also examined and a story was elicited in more formal settings with the help of a picture series from the research project COST Action IS0804. The narrative was compared with the interview to see if visual support improved the participants language. Results show that the multilinguals had a better result in their mother tongue than in Swedish. The multilingualism where on a comparable level with the monolinguals in their mother tongue. The multilinguals where on a slightly lower level in their Swedish compared to the monolinguals. The study showed that visual support might have improved the language of all the participants.

Bakgrund: Idag lever cirka 100 000 med Alzheimers sjukdom. Alzheimers är en av många demenstillstånd. Orsaken till uppkomsten av sjukdomen är i nuläget oklar. Riskerna att insjukna ökar bland annat med åldern och livsstil. Alzheimers är en anhörigsjukdom. Tidigare forskning visar att anhöriga upplever att relationen med personen med Alzheimers förändras samtidigt som det sker en rollförändring. Rollen som anhörigvårdare medför både fysisk och psykiskt påfrestning. Syfte: Syftet var att belysa upplevelsen av att vara anhörig vid Alzheimers sjukdom. Metod: En kvalitativ litteraturstudie med induktiv ansats av fem självbiografier. Resultat: Anhöriga upplever att rollen som anhörigvårdare är påtvingad eller som en äktenskaplig plikt. I samband med anhörigrollen upplevs känslor som skuld, maktlöshet, ensamhet och frustration. Anhöriga upplever att de ständigt måste anpassa sig till den sjuke och prioriterar inte sig själv, sin hälsa och sina behov. Slutsatser: Sjuksköterskor men även andra professioner behöver uppmärksamma anhöriga mer genom att lyssna och ta del av deras upplevelser. Sjuksköterskan har ett stort ansvar att organisera vård och omsorg till personer med Alzheimers sjukdom och stötta deras anhöriga.

The Alzheimer's Disease Life Events study examines whether there is a relationship between life events and Alzheimer's disease (AD). The ADLE study uses a mixed methods approach to answer the central research question:Are life events a risk factor for Alzheimer's disease? The central research question uses the following theory questions to examine:1. Is there a difference between the number of life events between patients and controls, using the Life Events and Difficulties Schedule (LEDS)(Brown and Harris, 1978) as a measurement tool?2. Is there a difference in the way (i.e. positive, neutral and negative) life events are discussed and in the range of emotions expressed when discussing life events between the patients and controls? 3. Are there any differences in the narrative constructions of life events, as interpreted by the Biographic Narrative Interpretive Method (BNIM)(Wengraf, 2001, 2008) between the patient and control groups? 4. Can the differences, between the patient and control groups, in the narratives be developed into a diagnostic marker? 5. Can the Emotion Word Coding (EWC)(Danner et aI., 2000) be used as a diagnostic marker by being applied to text collected from patients and controls over a period of decades? The ADLE study found that the patient group had experienced more life events in comparison with the control group as defined by the LEOS (Brown and Harris, 1978), and that the patient group had experienced more bereavements under the age of 51 years. The evidence supports the association between life events and AD.Even though there were significantly more life events experienced by the patients, the EWC (Danner et aI., 2001) found significantly fewer discussions expressing emotion bythe patients, particularly the negatively described ones. The range of negative and positive words used to describe the life events was significantly fewer too. This implies that the ways the patients express emotions about life events is substantially different from the controls. This finding was mirrored in the thematic field analysis of the BNIM interviews (Wengraf, 2001, 2008), which found differences in the content and structure of the narratives, and the emotional expression in the narratives about life events. A tool has been constructed using the differences between patients and controls to contribute to the early diagnosis of AD. In addition, the ADLE study has contributed to a gap in the knowledge about life events and AD.

Dementia, the most common cause of which is Alzheimer's disease (AD), currently affects 850,000 people in the UK, a figure set to rise to over 1 million by 2025. There is currently no disease modifying therapy available to slow or halt this progressive disease. Current understanding of AD implicates the neurotoxic amyloid-β (Aβ) peptide as the primary initiator in a cascade of events leading to the neuronal cell death and brain atrophy associated with the disease. Therefore, inhibiting the production or enhancing the clearance of Aβ within the brain has become a major target for the production of disease modifying therapeutics. Aβ is produced by brain cells through the sequential proteolytic cleavage of a larger transmembrane protein known as the amyloid precursor protein (APP) by β- and γ-secretases. Several aspects of APP physiology can influence its proteolysis, and thus Aβ production, including the isoform of APP which is expressed, its trafficking and subcellular location and its physical interactions with other proteins in the cellular environment. Here we have investigated the influence of subcellular trafficking and location and protein-protein interactions on the differential proteolysis of two APP isoforms, APP695 and APP751 in a neuroblastoma cell line. We have shown that APP751 undergoes less amyloidogenic proteolysis than APP695 and that retention within the early secretory pathway may contribute to this difference. APP751 shows higher co-localisation to the trans-Golgi network than APP695 in immunofluorescence microscopy studies, while addition of a mutation which causes APP proteolysis in the secretory pathway reduces the large difference in amyloidogenic proteolysis of these two isoforms. Targeting APP endocytosis from the cell surface, thought to be a key determinant in Aβ generation, effects APP isoform proteolysis and Aβ production to a similar extent in both the APP isoforms suggesting differences in proteolysis occur before this trafficking event. We also show by immunoblot analysis that the APP isoforms may be differentially cleaved by proteases other than β- and γ-secretase to produce recently identified proteolytic fragments. Using a liquid chromatography - tandem mass spectrometry approach coupled to prior stable isotope labelling of amino acids in cell culture (SILAC), we have identified the interactomes of the two APP isoforms in our model system. Gene ontology analysis identified enrichment of nuclear and mitochondrial proteins specifically in the APP695 interactome. Using siRNA mediated protein knockdown, we have shown interactions with Fe65 and ataxin-10 specifically influence Aβ generation from the APP695 isoform. Fe65 alters proteolysis at the rate limiting β-secretase cleavage step, while ataxin-10 alters proteolysis by γ-secretase. Interaction with growth-associated protein 43 specifically influences Aβ generation from the APP751 isoform, altering proteolysis at the γ-secretase step. Finally we have shown that recently discovered familial AD-linked mutation and protective mutation within the Aβ region of the APP protein have consistent effects on APP proteolysis in both the APP isoforms.

Alzheimers sjukdom är en kronisk och obotlig neurodegenerativ sjukdom. Sjukdomen kommer smygandes och drabbar individer sent i livet. En av flera riskfaktorer för att utveckla Alzheimers sjukdom är hyperkolesterolemi. Hyperkolesterolemi kan orsaka en ökad syntes av amyloid-β i hjärnan. Proteinet aggregeras, bildar plack och orsakar celldöd i hjärnan. Syftet med arbetet var att utvärdera om statiner har en effekt på försämrad kognition, en klinisk bild som ses hos patienter med Alzheimers sjukdom. Utvärderingen gjordes efter att vetenskapliga studier sammanställts. Studier har gjorts och görs än idag för att se om en hämmad kolesterolsyntes i hjärnan kan minska syntesen av amyloid-β och därmed reducera risken för att utveckla Alzheimers sjukdom. Alzheimers sjukdom är en komplicerad sjukdom med en oklar sjukdomsorsak och otydliga stadium innan diagnos. Detta försvårar utförandet av studier med ändamål för att utvärdera om statiner kan reducera risken för sjukdomen. Idag finns djur- och humanstudier som visar på olika resultat, både att statiner har en positiv effekt på nedsatt kognition och amyloid-β men även att statiner inte har en effekt på Alzheimers sjukdom.

<p>Cirka 150 000 personer drabbas av Alzheimers sjukdom i Sverige och en stor del av dem vårdas av sina närstående. Sjukdomen förändrar livssituationen både för den drabbade och för dennes familj. Syftet med studien har varit att beskriva närståendes upplevelser av att leva med en Alzheimerssjuk person, tolkat i ljuset av copingteorier, för förståelse av hur närstående lättare kan hantera svårigheter. Metoden utgår från en kvalitativ ansats med induktiv tematisk analys för biografier och analytisk induktion för intervju. I resultaten synliggörs närståendes förnekande vid tidiga tecken på sjukdomen, men sjukdomens ökande försämring leder så småningom till accepterande av sjukdomen. Närståendes upplevelser präglas även av ilska, sorg, ensamhet och stress samt skuldkänsla, men också av gemenskap och kärlek till den sjuke. I diskussionen framhålls att närstående till Alzheimerssjuka personer behöver stöd, hjälp och information om sjukdomen. För framtida studier föreslås hur man kan uppmuntra närstående till att söka olika sorters stöd.</p>

<p><strong>Bakgrund:</strong> Alzheimers sjukdom är en demenssjukdom som har kommit att bli en folksjukdom då antalet insjuknade ökar stadigt i takt med att befolkningen blir allt äldre. De anhöriga får ofta inträda som vårdare i hemmet och sjukdomen ger minst lika mycket lidande för den anhörige som för den sjuke. Detta kan leda till både psykisk och fysisk ohälsa hos de anhöriga. <strong>Syfte:</strong> Syftet med denna studie var att belysa anhörigas upplevelser av att leva med en person med Alzheimers sjukdom. <strong>Metod:</strong> Metoden för studien var en litteraturstudie med kvalitativ ansats. Fyra självbiografier analyserades utifrån en manifest innehållsanalys. <strong>Resultat:</strong> Resultatet sammanställdes i tre kategorier: <em>Sorg, en förändrad livssituation </em>och<em> ljuspunkter i vardagen. </em>Resultatet visade att de anhöriga gick igenom ett sorgearbete när deras livskamrat drabbades av sjukdomen och de hade svårt att acceptera sjukdomen. De anhöriga upplevde en radikal förändring av livssituationen på grund av sjukdomen och de fick inträda som vårdare för att ständigt finnas där för den sjuke. Trots detta upplevde de anhöriga att det fortfarande förekom ljuspunkter i livet, stöd från vänner och familj visade sig vara viktigt.<strong> Slutsats: </strong>Resultatet kan öka sjuksköterskans förståelse för hur de anhöriga upplever sin situation vilket kan göra att stöd erbjuds i ett tidigt skede.<strong></strong></p>

The processing of amyloid precursor protein (APP) by - and -secretases produces amyloid (A) peptide, the principal component of the neuritic plaques found in Alzheimers disease (AD) pathology. The enzyme -secretase is a multimeric protein consisting of presenilins-1/2 (PS1/PS2), nicastrin, anterior pharynx defective 1 (APH-1) and presenilin enhancer-2 (PEN-2). Recently it was discovered that p23, a transmembrane protein involved in intracellular protein trafficking, negatively regulates -secretase activity. In the present study, I evaluated the levels/expression of the nicastrin and p23 and their possible colocalization with PS1 in normal adult and developing brains. Additionally, I have studied the alterations of p23 levels in both animal model of neurodegeneration and in postmortem AD brains. Nicastrin and p23 were widely distributed throughout the brain and colocalized in all brain regions with PS1. The levels of nicastrin and p23 were relatively high at the early stages of postnatal development and then declined gradually as age increased. Interestingly, p23 level/expression was found to be altered following kainic acid-induced neurodegeneration in the adult rat brain. Additionally, p23 levels were reduced in the brains of individuals with AD. These results, taken together, suggest that both nicastrin and p23 are expressed in neurons throughout the brain and their levels decline gradually during development to reach an adult profile. Additionally, my results indicate that a decreased level of p23 may contribute to AD pathogenesis by increasing the production of A-related peptides.