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Updated: Feb 3, 2019


 

1. How does diabetes accelerate Alzheimer disease pathology?

Conclusions & Relevance: Alzheimer disease (AD) and diabetes are both associated with enormous and increasing socioeconomic effects. Diabetes affects the processing of amyloid-β and tau, and may increase the rate of formation of senile plaques and neurofibrillary tangles. Hyperinsulinemia is associated with amyloid-β accumulation and regulates tau phosphorylation. Oxidative stress activates inflammatory pathways and, hence, might exacerbate AD neuropathology. Mitochondrial dysfunction is associated with both diabetes and AD, and leads to intracellular calcium dysregulation and abnormal processing of the amyloid precursor protein. Induction of diabetes exacerbates AD neuropathology in mouse models of this neurodegenerative disease

Citation: Nature Reviews Neurology volume6, pages551–559 (2010)


 

2. Defective Insulin Signaling, and Mitochondrial Dysfunction as Common Molecular Denominators Connecting Type 2 Diabetes to Alzheimer Disease

Conclusion & Relevance: The emergence of molecular links between inflammatory, deregulated insulin signaling and mitochondrial dysfunction in AD and diabetes raises the prospect for development of novel therapeutic strategies for AD based on antidiabetes and/or anti-inflammatory agents

Citation: Fernanda G. De Felice and Sergio T. Ferreira.Diabetes 2014 Jun; DB_131954.https://doi.org/10.2337/db13-1954


 

3. A Molecular Link between Type 2 Diabetes and Alzheimer Disease

Conclusion & Relevance: In summary, we show for the first time that formation of local IAPP amyloid (islet amyloid polypeptide) can be accelerated by hematogenous seed of synthetic IAPP and proIAPP fibrils. We also show that heterologous seeding with Aβ fibrils is possible. From our studies of patient material, we have found that islet IAPP amyloid does not recruit Aβ, but that cerebral Aβ amyloid contains IAPP.

Citation: The American Journal of Pathology.Volume 185, Issue 3, March 2015, Pages 834-846


 

4. Insulin as a bridge between type 2 diabetes and Alzheimer disease – how antidiabetics could be a solution for dementia.

Conclusion & Relevance: Type 2 diabetes patients often develop some form of dementia (such as AD), whereas AD patients may also present hyperglycemia, hypercholesterolemia, and insulin signaling dysfunction (common features to T2D). Thus, it has been increasingly suggested that several anti-T2D drugs may have a therapeutic potential in dementia, with some of them already under clinical analysis for that purpose. In fact, some of the above-mentioned anti-diabetics were beneficial against some AD hallmarks, e.g., Aβ plaque formation and tau hyperphosphorylation. Some of them also promoted neurogenesis and cell proliferation, and reduced neuroinflammation and cell death.

Citation: Front. Endocrinol., 08 July 2014. https://doi.org/10.3389/fendo.2014.00110


 

5. Impaired Cerebral Autoregulation-A Common Neurovascular Pathway in Diabetes may Play a Critical Role in Diabetes-Related Alzheimer’s Disease

Conclusion & Relevance: AD and T2D are age dependent diseases. There are several potential mechanisms that have been proposed to be involved in the pathogenesis of AD including classical Aβ protein deposition, tau associated neurofibrillary tangles as well as the acetylcholine deficiency. Previous generations of treatment focusing on these mechanisms have failed to prevent the progression of AD, giving rise to the need for alternative therapeutic approaches. Recent studies have suggested that insulin resistance and cerebral autoregulation could be responsible for common pathogenesis in comorbid AD and Diabetes. It is possible that impaired autoregulation is occurring very early before the onset of dementia. Whether this cerebral vascular dysfunction precedes neurodegeneration or whether it is simply an outcome of amyloid and tau deposition has yet to be validated. In order to identify this pathology and even to develop therapeutic interventions there is a great need for more inclusive studies.

Citation: Curr Res Diabetes Obes J. 2017 Jun; 2(3): 555587.



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1. Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains

a. Conclusions and Relevance: In this study, altered AQP4 expression was associated with aging brains. Loss of perivascular AQP4 localization may be a factor that renders the aging brain vulnerable to the mis-aggregation of proteins, such as amyloid-β, in neurodegenerative conditions such as AD.

b. Citation: JAMA Neurology. 2017;74(1):91-99. doi:10.1001/jamaneurol.2016.4370


 

2. Association of Amyloid Pathology With Myelin Alteration in Preclinical Alzheimer Disease

a. Conclusions and Relevance: The accumulation of aggregated β-amyloid and tau proteins into plaques and tangles is a central feature of Alzheimer disease (AD). While plaque and tangle accumulation likely contributes to neuron and synapse loss, disease-related changes to oligodendrocytes and myelin are also suspected of playing a role in development of AD dementia.These findings suggest amyloid pathologies significantly influence white matter and that these abnormalities may signify an early feature of the disease process. We expect that clarifying the nature of myelin damage in preclinical AD may be informative on the disease’s course and lead to new markers of efficacy for prevention and treatment trials.

Citation: JAMA Neurology. 2017;74(1):41-49. doi:10.1001/jamaneurol.2016.3232


 

3. R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family-Clinical, Genetic, and Neuropathological Study

a.Conclusion & Relevance: The R47H variant in the triggering receptor expressed on myeloid cells 2 gene (TREM2), a modulator of the immune response of microglia, is a strong genetic risk factor for Alzheimer disease (AD) and possibly other neurodegenerative disorders. Our results demonstrate a complex genetic landscape of LOAD, even in a single pedigree with an apparent autosomal dominant pattern of inheritance. Our findings support the role of the TREM2 receptor in microglial clearance of aggregation-prone proteins that is compromised in R47H carriers and may accelerate the course of disease.

b.Citation: JAMA Neurology. 2015;72(8):920-927. doi:10.1001/jamaneurol.2015.0979


 

4.Biomarkers for Insulin Resistance and Inflammation and the risk for Alzheimer Disease

a.Conclusions & Relevance: Our study shows that an innate pro-inflammatory cytokine response in middle age significantly contributes to AD. As these risk factors cluster in families, it is important to realize that early interventions could prevent late-onset AD. One could argue for a high-risk–prevention strategy by identifying the offspring of patients with AD, screening them for hypertension and vascular factors, and implementing various preventative health measures.

b.Citation: Arch Neurol. 2012;69(5):594-600. doi:10.1001/archneurol.2011.670


 

5.Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease

a.Conclusions and Relevance: Our findings demonstrate genetic overlap between AD and immune-mediated diseases and suggest that immune system processes influence AD pathogenesis and progression. We have identified genetic overlap between AD and immune-mediated diseases, implicating the HLA locus and IPMK in the pathobiology of AD. These findings provide novel insights into the relationship between inflammation and AD. Building on prior genetic and molecular evidence,31 our results are consistent with the hypothesis that rather than representing a downstream effect of neurodegeneration, inflammation influences AD pathogenesis and progression, which may have implications for treatment and prevention strategies in AD.

b.Citation: JAMA Neurol. 2016;73(6):691-697. doi:10.1001/jamaneurol.2016.0150

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Updated: Nov 1, 2018


 

1.The Role of Cardiovascular Risk Factors and Stroke in Familial Alzheimer Disease

a.Conclusion & Relevance: In familial and sporadic LOAD (late onset Alzheimer’s disease), a history of stroke was significantly associated with increased disease risk and mediated the association between selected cardiovascular risk factors and LOAD, which appears to be independent of the LOAD-related genetic background.

b.Citation: JAMA Neurology. 2016;73(10):1231-1237. doi:10.1001/jamaneurol.2016.2539


 

2. Interactive effects of vascular risk burden and advanced age on cerebral blood flow

a.Conclusion & Relevance: Among older adults with multiple vascular risk factors, we found association between advancing age and reduction in cerebral blood flow in cortical regions implicated in early AD. Finally, the present results highlight the potential utility of interventions designed to treat reduced CBF in older adults who present with vascular risk factors. Given that many vascular risk factors such as diabetes and smoking can be treated, interventions designed to target vascular risk factors in order to maintain CBF may represent important opportunities for preventing or delaying the onset of cognitive impairment and dementia.

b. Citation: Front. Aging Neurosci., 07 July 2014 | https://doi.org/10.3389/fnagi.2014.00159


 

3.Clinical Predictors of Severe Cerebral Amyloid Angiopathy and Influence of APOE Genotype in Persons With Pathologically Verified Alzheimer Disease

a.Conclusions & Relevance: Being Hispanic and having a history of transient ischemic attack-like events were significant clinical predictors for the presence of severe cerebral amyloid angiopathy in persons found to have Alzheimer’s disease, via neuropathological examination years later. Hispanic ethnicity is a sociocultural construct representing persons of disparate genetic origins, so the biological implications of this observation are unclear and warrant further investigation. These associations may help clinicians identify persons with cognitive impairment at risk for harboring severe CAA for whom anticoagulation may be contraindicated. Interestingly, we found a lower degree of diffuse amyloid plaque pathology in persons with severe CAA, suggesting differences in Aβ trafficking associated with CAA. The distinct characteristics of APOE ε4–related and non–APOE ε4–related CAA support pathological and genetic studies that suggest divergent sociocultural and pathophysiological mechanisms.

b.Citation: JAMA Neurology. 2014;71(7):878-883. doi:10.1001/jamaneurol.2014.681


 

4.Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre

a.Conclusion & Relevance: Our study confirms the prevalence of cerebrovascular disease in Alzheimer’s disease and the additive or interactive deleterious effect of Alzheimer’s disease pathology and cerebrovascular disease on cognition, and adds further evidence on the effect of Alzheimer’s disease pathology to produce clinical symptoms. Our results indicate that cerebrovascular disease has an additive effect increasing the risk of dementia in Alzheimer’s disease, although the effect is more prominent in earlier stages.An implication of this study is that in the absence of any specific disease-modifying treatments for Alzheimer’s disease in the near future, we urge, based on the high prevalence on cerebrovascular disease described in our data here, that aggressive management of vascular risk factors and encouragement of healthy lifestyles in midlife may have benefit for Alzheimer’s disease or α-synucleinopathy individuals at increased risk to become clinically symptomatic, and probably to those with other causes of cognitive impairment. Indeed, even those who already manifest the clinical features of Alzheimer’s disease or α-synucleinopathy may benefit from effective therapies that mitigate vascular risk factors and cerebrovascular disease. Guidelines for treatment and prevention of vascular contributions to dementia are available. Finally, we propose that it is timely to consider inclusion of patients with vascular risk factors, cardiovascular disease and cerebrovascular disease in clinical studies as these cases are often excluded currently, but they account for a large percentage of the subjects with dementia and thereby more accurately embody the challenges we must face in developing disease-modifying therapies for Alzheimer’s disease.

b.Citation: Brain, Volume 136, Issue 9, 1 September 2013, Pages 2697–2706,https://doi.org/10.1093/brain/awt188


 

5.Does vascular pathology contribute to Alzheimer changes?

a.Conclusions & Relevance: The presence of vascular pathology involving arterial stiffness, arteriolosclerosis, endothelial degeneration and blood–brain barrier dysfunction leads to chronic cerebral hypoperfusion. Pathological changes in human brain and animal studies suggest cerebral hypoperfusion which in turn induces several features of AD pathology including selective brain atrophy, white matter changes and accumulation of abnormal proteins such as amyloid β. Cerebral pathological changes may be further modified by genetic factors such as the apoliopoprotein E ε4 allele. Further support for the notion that vascular pathology influences AD changes is provided by the evidence that interventions which improve vascular function attenuate AD pathology.

Citation:Journal of the Neurological Sciences, Volume 322, Issues 1–2, 15 November 2012, Pages 141-147, https://doi.org/10.1016/j.jns.2012.07.032

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