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Alzheimer's & Vascular Diseases: A Case for Combination Therapy

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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