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.

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.

My dad had early onset Alzheimer’s disease. I first knew something was wrong with him in 1995. He was 49 then, and I was just about to start the eighth grade. That’s the summer his company backed him into a corner and told him to quit or be fired. He had worked there 14 years. They said his behavior was changing, and they thought he was doing it on purpose. It took seven years to get an actual diagnosis. The doctors looked for everything. They just thought he was too young. I’ve relied on materials found in my parents’ house from those days. But I’ve also let my imagination run, and added some forms of my own. Besides, isn’t life just one series of what actually happened and then the years we spend looking backward at our own memories trying to sort it out? This is my Dad’s story. And, it’s my story too.

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Indiana University-Purdue University Indianapolis (IUPUI) / Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a receptor expressed in myeloid cells including microglia in brain and osteoclasts in bone has been proposed as a link between brain and bone disease. Previous studies identified an AD-associated mutation (R47H) which is known to confer an increased risk for developing AD. In these studies, we used a heterozygous model of the TREM2 R47H variant (TREM2R47H/+), which does not exhibit cognitive defects, as a translational model of genetic risk factors that contribute to AD, and investigated whether alterations to TREM2 signaling could also contribute to bone and skeletal muscle loss, independently of central nervous system defects. Our study found that female TREM2R47H/+ animals experience bone loss in the femoral mid-diaphysis between 4 and 13 months of age as measured by microCT, which stalls out by 20 months of age. Female TREM2R47H/+ animals also experience significant decreases in the mechanical and material properties of the femur measured by three-point bending at 13 months of age, but not at 4 or 20 months. Interestingly, male TREM2R47H/+ animals do not demonstrate any discernable differences in bone geometry or strength until 20 months of age, where we observed slight changes in the bone volume and material properties of male TREM2R47H/+ bones. Ex vivo osteoclast differentiation assays demonstrate that only male TREM2R47H/+ osteoclasts differentiate more after 7 days with osteoclast differentiation factors compared to WT, but qPCR follow-up showed sexdependent differences in intracellular signaling. However, bone is not the only musculoskeletal tissue affected by the TREM2 R47H variant. Skeletal muscle strength measured by both in vivo plantar flexion and ex vivo contractility of the soleus is increased and body composition is altered in female TREM2R47H/+ mice compared to WT, and this is not likely due to bone-muscle crosstalk. These studies suggests that TREM2 R47H expression in the bone and skeletal muscle are likely impacting each tissue independently. These data demonstrate that AD-associated variants in TREM2 can alter bone and skeletal muscle strength in a sex-dimorphic manner independent of the presence of central neuropathology.

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Alzheimer's disease affects many people worldwide and is often cared for by a family member. It is not uncommon for family members to become caregivers. The aim was to describe the experiences of family caregivers in caring for a loved one with Alzheimer's disease. The method used was a literature review with a qualitative approach, conducted using Polit and Beck's (2020) nine-step model. Ten articles were identified and analyzed using thematic analysis. Results: The analysis resulted in three main themes and seven subthemes: Emotional reactions with subthemes: Transition from family member to caregiver, during the progression of the disease, fear for the future. The caregiver role with subthemes: Responsibility and duty, challenges and sacrifices, and the theme Need for knowledge and support and with the subthemes: Knowledge and Support. The conclusion shows that family members caring for their loved ones with Alzheimer's experience difficulties in handling the caregiver role, both emotionally and instrumentally. They often experience a lack of support from the healthcare system, highlighting the importance of nurses applying family-centered care. Suggestions for further research: Developing interventions to implement family-centered care.

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