Risk of developing dementia in people with diabetes and mild cognitive impairment

Velayudhan, Latha; Poppe, Michaela; Archer, Nicola; Proitsi, Petroula; Brown, Richard G.; Lovestone, Simon

doi:10.1192/bjp.bp.109.067942

Cited by 118 publications

(84 citation statements)

References 27 publications

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“…How diabetes mellitus affects Aβ catabo lism and AD risk is not yet well understood. Patients with diabetes mellitus are estimated to be 1.4-2.0-fold more likely than healthy individuals to develop AD 72,73 , although these claims need to be verified in patients with biomarker-confirmed AD. In patients with diabetes mellitus, insulin resistance substantially compromises the positive effects of insulin on both cognition and hepatic clearance of circulating Aβ 74,75 , resulting in AD-like alterations in the brain.…”

Section: Metabolic Disordersmentioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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The global burden of Alzheimer disease (AD), already the most common type of dementia, is expected to increase still further owing to population ageing. AD not only causes severe distress for patients and caregivers, but also results in a large economic burden on society. Current major challenges in AD include the lack of reliable biomarkers for its early diagnosis, as well as the lack of effective preventive strategies and treatments 1,2 . Thus, increased understanding of the molecular patho genesis of AD could lead to the development of improved diagnostic and therapeutic strategies.AD is conventionally regarded as a CNS disorder. However, increasing experimental, epidemiological and clinical evidence has suggested that manifestations of AD extend beyond the brain. These systemic alterations might not be simply secondary effects of the cerebral degeneration seen in AD, but could reflect under lying processes linked to progression of the disease. AD pathogenesis is complex, involving abnormal amyloid-β (Aβ) metabolism, tau hyperphosphorylation, oxidative stress, reactive glial and microglial changes, and other pathological events. Given that Aβ is a major hallmark of AD and a fertile area of research in this disease, this Review focuses on the systemic role of Aβ in AD. We discuss the communication between peripheral and central pools of Aβ, and describe interactions between systemic abnormalities and AD pathogenesis in the brain. We review emerging findings of associations between systemic abnormalities and Aβ metabolism, and describe how these associations might interact with or reflect on the central pathways of Aβ production and clearance. On the basis of these findings, we suggest that interactions between the brain and the periphery might have a crucial role in the development and progression of AD. Aβ biogenesis and catabolismA steady accrual of data from laboratories and clinics is providing increasing support for the concept that an imbalance between the production and clearance of Aβ is a very early (and often initiating) factor in AD 3 . Normal metabolism of Aβ and maintenance of the homeostatic balance between Aβ production and clearance is, therefore, essential to maintain brain health. In fact, physiological metabolism of Aβ occurs not only in the brain but also in the periphery, and communication between these regions is possible (FIG. 1). Central and peripheral production of AβAβ is derived from the proteolytic cleavage of amyloid precursor protein (APP), which is expressed not only in brain cells, including neurons, astrocytes and microglia, but also in peripheral organs and tissues, such as the Abstract | Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becom...

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Section: Metabolic Disordersmentioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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“…Although not all research results are in agreement, the majority of the data suggests that diabetics, specifically T2D subjects, are at much higher risk of developing AD than normal subjects. Elderly people with diabetes have an especially increased risk of mild cognitive impairment (MCI) [18] and an association of diabetes with MCI varies with amyloid subtype (amnestic) MCI and nonamnestic MCI) and number of domains, and with the sex of the patient, with females being more susceptible than males [19]. Diabetes as a significant risk factor for dementia or AD has been clearly established by studies in the US [20] and several other countries (Taiwan [21], China [22], Japan [23], and Finland [24]).…”

Section: Clinical Manifestationsmentioning

confidence: 99%

“…Numerous studies have documented a strong association between diabetes and Alzheimer's Disease (AD) [16], [17], [18], [19], [20], [44]. However, the mechanisms underlying this association have not been clearly established.…”

Section: Pathophysiologymentioning

confidence: 99%

Metabolic relationship between diabetes and Alzheimer's Disease affected by Cyclo(His-Pro) plus zinc treatment

et al. 2017

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BackgroundAssociation of Alzheimer's Disease (AD) with Type 2 Diabetes (T2D) has been well established. Cyclo(His-Pro) plus zinc (Cyclo-Z) treatment ameliorated diabetes in rats and similar improvements have been seen in human patients. Treatment of amyloid precursor protein (APP) transgenic mice with Cyclo-Z exhibited memory improvements and significantly reduced Aβ-40 and Aβ-42 protein levels in the brain tissues of the mice.Scope of reviewMetabolic relationship between AD and T2D will be described with particular attention to insulin sensitivity and Aβ degradation in brain and plasma tissues. Mechanistic effect of insulin degrading enzyme (IDE) in decreasing blood glucose and brain Aβ levels will be elucidated. Cyclo-Z effects on these biochemical parameters will be discussed.Major conclusionStimulation of IDE synthesis is effective for the clinical treatment of metabolic diseases including AD and T2D.General significanceCyclo-Z might be the effective treatment of AD and T2D by stimulating IDE synthesis.

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“…Besides the well-known connection between T2DM and peripheral nervous system disease, the diabetes-induced lesions in the central nervous system (CNS), such as cerebrovascular disease and cognitive dysfunction, are receiving increased attention. Several epidemiological studies have found that T2DM is an independent risk factor for both Alzheimer's disease (AD) and vascular dementia (VaD) [1,2]. In addition, further research has shown that T2DM may also exercise influence on the prevalence of mild cognitive impairment (MCI), which is considered a pre-clinical stage of dementia.…”

Section: Introductionmentioning

confidence: 99%

Clinical Characteristics for the Relationship between Type-2 Diabetes Mellitus and Cognitive Impairment: A Cross-Sectional Study

Zhou

Fang

Liu³

et al. 2015

Aging and disease

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ABSTRACT:We explored the potential differences in cognitive status, lipid and glucose metabolism, ApoEε4 alleles and imaging between diabetic and non-diabetic subjects. 83 subjects with normal cognitive function and 114 mild cognitive impaired patients were divided into four groups by history of diabetes. General demographics was collected from all participants followed by MRI scan, biochemical examinations and a series of neuropsychological tests. Student's t test, multiple regressions and one-way ANOVA were applied to investigate the differences between groups. Comparing diabetic patients with non-diabetic subjects in the mild cognitive impaired group, we found several decreased items in recall of three words in MMSE (p=0.020), AVLT and SCWT (p＜0.050). The multiple linear regression revealed that two-hour glucose level (B= -0.255，p＜0.001) and fasting C-peptide (B= -0.466， p=0.001) had negative effects on the score of MMSE. In addition, diabetic patients treated with insulin and other diabetes medication performed better in part of the AVLT (p＜0.050) compared to patients with insulin treatment or oral antidiabetic medication only. Patients with metformin medication had a better memory outcome compared to patients with sulphonylurea medication in the AVLT long delay free recall (p =0.010). These findings show that patients of mild cognitive impairment with diabetes mellitus have a worse outcome in attention, information processing speed and memory compared to non-diabetic patients. Higher two-hour glucose level and C-peptide level may be risk factors for severe cognitive impairment in type-2 diabetes mellitus patients. The results of this study also suggest that medication may have effects on cognitive function.Key words: Type-2 diabetes mellitus, mild cognitive impairment, C-peptide, blood glucoseThe incidence of type-2 diabetes mellitus (T2DM) in China has dramatically increased in the last decade. Besides the well-known connection between T2DM and peripheral nervous system disease, the diabetes-induced lesions in the central nervous system (CNS), such as cerebrovascular disease and cognitive dysfunction, are receiving increased attention. Several epidemiological studies have found that T2DM is an independent risk factor for both Alzheimer's disease (AD) and vascular dementia (VaD) [1,2]. In addition, further research has shown that T2DM may also exercise influence on the prevalence of mild cognitive impairment (MCI), which is considered a pre-clinical stage of dementia. In Luchsinger and colleagues' study [3], the results indicated that diabetes mellitus is related to a relatively higher risk for all causes of MCI (about 1.5 fold). In another recent metaanalysis report, diabetes was shown to have higher risk for any dementia and MCI (1.46 for AD, 2.48 for VaD and 1.21 for MCI) [4].The present studies have confirmed that T2DM is a robust risk factor for cognitive dysfunction. However, the precise mechanisms remain to be elucidated [5]. A wide range of metabolic and vascular disturbances have been proposed to e...

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Risk of developing dementia in people with diabetes and mild cognitive impairment

Abstract: Diabetes mellitus increases not only the risks of dementia and mild cognitive impairment but also the risk of progression from such impairment to dementia.

Cited by 118 publications

References 27 publications

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

Metabolic relationship between diabetes and Alzheimer's Disease affected by Cyclo(His-Pro) plus zinc treatment

Clinical Characteristics for the Relationship between Type-2 Diabetes Mellitus and Cognitive Impairment: A Cross-Sectional Study

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