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• W4313880105 abstract "Possible mechanisms of Alzheimer's disease-related cognitive impairment in patients with diabetes mellitus are shown in this figure. DPP-4i may modulate Aβ accumulation in the process of AD-related cognitive impairment. Several epidemiological studies and meta-analyses1, 2 have indicated that diabetes mellitus increases the risk of Alzheimer's disease (AD) incidence by 1.5- to 2-fold. While amyloid β (Aβ) deposition in the brain is regarded as a major pathological feature of AD, it is often observed to coexist with cerebral small vessel disease (SVD), and the contribution of traditional vascular risk factors, including diabetes mellitus, is also important during the course of the incidence of Alzheimer's disease. It has been estimated that it takes approximately 20–30 years from the start of Aβ accumulation to the incidence of dementia. Therefore, in routine clinical practice, suppressing Aβ production and promoting Aβ excretion in the early stages are important therapeutic strategies for preventing the incidence of dementia. Possible mechanisms for an association between Alzheimer's disease and diabetes mellitus include insulin resistance, abnormal insulin signaling, inflammation and oxidative stress, progression of cerebral SVD, and abnormal amyloid-β metabolism (Figure 1). It has been suggested that dipeptidyl peptidase-4 inhibitor (DPP-4i) drugs used for treating diabetes mellitus provide neuroprotection as a pleiotropic effect, and recent clinical research has demonstrated that DPP-4i use suppresses cognitive decline in the elderly with mild cognitive impairment (MCI) or Alzheimer's disease. However, no research had focused on imaging and pathological findings. The authors therefore examined the effects of DPP-4i agents on cognitive function in elderly patients with diabetes mellitus with AD-related cognitive impairment who were Aβ positron emission tomography (PET) positive. The most important finding of this study was significantly less Aβ accumulation in patients with diabetes mellitus taking DPP-4i drugs compared with patients with diabetes mellitus not taking them3. The results also suggested that cognitive decline was slower in patients with diabetes mellitus using DPP-4i agents than in those not using them. Since DPP-4i agents do not pass through the blood–brain barrier (BBB), it is likely that their effect was indirect, resulting from increased glucagon-like peptide-1 (GLP-1) levels in the peripheral circulation. It has been suggested that GLP-1 receptor agonists, which can cross the BBB, have the effect of improving vascular endothelial function, and if this improves the possible mechanism of Aβ excretion described later, Aβ accumulation may be reduced. It has also been suggested that DPP-4is regulate Aβ accumulation during the course of Alzheimer's disease, but a precise mechanism remains unknown. It had been thought that the Aβ clearance pathway involved drainage into the blood and cerebrospinal fluid, but recent research has suggested the existence of a perivascular lymphatic drainage pathway4. In order to maintain Aβ clearance in a normal state, it is important to preserve arterial stiffness at the cerebral microvessel level. In this regard, it has been suggested that patients with diabetes mellitus are susceptible to impaired vasodilatation, and that vascular endothelial dysfunction may promote BBB permeability, and contribute to the development of cerebral small vessel lesions in these patients5. Regarding a relationship between plasma Aβ concentration and SVD, based on our research results, higher levels of plasma Aβ were associated with an increased number of silent brain infarctions and the presence of cerebral microbleeds, but it was not clear if plasma Aβ levels were associated with white matter lesions. As previous findings regarding a relationship between plasma Aβ concentrations and white matter lesions have been inconsistent, further prospective studies will be needed to clarify if there is an association or not. Interestingly, in this study, the global Aβ burden was lower in diabetic patients with AD-related cognitive impairment taking DPP-4is than in non-diabetic patients with AD-related cognitive impairment. Since experiments in mice have shown that a high-fat diet promotes Aβ accumulation6, future research should examine whether strict dietary therapy and DPP-4i treatment from the early phase could prevent the incidence of Alzheimer's disease. The results of several retrospective longitudinal studies provide support for a protective effect of DPP-4i on cognitive function in MCI and patients with Alzheimer's disease, while the APOE ε4 genotype may have modified the relationship between DPP-4i and deterioration of memory. It has been noted that the APOE 4 allele regulates Aβ excretion7, which could be one explanation for the risk of incident dementia increasing in patients with diabetes mellitus with the APOE 4 allele. Regarding associations of diabetes mellitus and Alzheimer's disease, it has been reported that there was significant atrophy in the medial temporal lobe, including the hippocampus and amygdala, in patients with diabetes mellitus compared with non-diabetic patients8 and an association between medial temporal lobe atrophy and insulin resistance was also demonstrated9. Regarding prevention, as it remains unclear whether the administration of drugs with neuroprotective effects (DPP-4i, GLP-1 receptor agonists etc.) would reduce the incidence and progression of small vessel disease or the progression of brain atrophy, it will be necessary to explore the respective associations in prospective research. As the present research is retrospective and cross-sectional in design, longitudinal examination of amyloid imaging over time would be needed to show causality and, for assessing cognitive function, skill in evaluating frontal lobe function, and other aspects would also be required. To demonstrate the neuroprotective properties of DPP-4is, clinical randomized control trials are warranted. The authors declare no conflict of interest. Approval of the research protocol: N/A. Informed consent: N/A. Registry and the registration No. of the study/trial: N/A. Animal studies: N/A." @default.
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• W4313880105 date "2023-01-08" @default.
• W4313880105 modified "2023-09-26" @default.
• W4313880105 title "Neuroprotective properties of <scp>DPP</scp>‐4i: A therapeutic target for dementia prevention in elderly diabetic patients?" @default.
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• W4313880105 doi "https://doi.org/10.1111/jdi.13972" @default.
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