Alzheimer’s disease (AD) is a progressive neurodegenerative disease that presents with memory loss in the early stages and progresses to total cognitive decline, loss of survival skills, and ultimately death in the later stages. amyloid-β ,Aβ) deposition to form senile plaques, intracellular phosphorylated tau protein aggregation to form neurofibrillary tangles, and massive neuronal and synaptic apoptosis.
Depending on the pathogenesis, AD can be divided into two main groups, one is familial, mainly because these individuals have amyloid-β protein precursor (AβPP), presenilin-1 (PS1), and presenilin-2 (PS2) genes in their genes, which account for less than 5% of the population; The other group is the epidemic type, which accounts for more than 95% of cases and is mainly associated with risk factors such as age, education, and the presence of the apolipoprotein E (APOE) gene.
In the past decades, a large number of studies have shown that type 2 diabetes mellitus (T2DM) may be another important risk factor for disseminated AD. A large number of epidemiological studies have shown that T2DM can increase the incidence of AD in patients. Basic studies have also shown that insulin resistance, the most important pathogenesis of T2DM, and the phenomenon of impaired insulin signaling play an important role in the development of AD. Therefore, glucose-lowering drugs may be a new target for the treatment of AD. This paper reviews the effects of T2DM on AD and the potential mechanisms of action, as well as the progress of research on the treatment of AD with glucose-lowering drugs.
Large epidemiological studies on the increased incidence of AD in T2DM
Several epidemiological studies have found a positive association between T2DM and the incidence of AD. In the 1990s, the Rotterdam Study, the first large epidemiological investigation to explore the association between T2DM and dementia, included 6,370 study subjects with a mean follow-up of 2.1 years, and the final results showed that after correcting for other confounding factors such as age and gender, people with T2DM were almost as likely to have dementia and The final results showed that after correcting for other confounding factors such as age and gender, people with T2DM were almost twice as likely to have dementia and AD as normal people, with a risk ratio (relative risk, RR) of 1.9, and the risk of AD was highest among those who chose insulin therapy, with an RR of 4.3, suggesting that the increased risk of AD in diabetes may be associated with high insulin levels, or possibly because people on insulin therapy have more severe disease and longer disease duration.
Subsequently, there are a number of relevant large epidemiological findings that support this conclusion.Peila et al2 found that the diabetes-AD association was influenced by the APOEε4 allele. The researchers followed 2,574 Japanese Americans living on the island of Hawaii for 3 years and found an RR:1.8 for the development of AD with diabetes alone, but a significantly increased risk of 5.5 when the APOEε4 allele was combined with diabetes. The number of senile plaques and the degree of neurofibrillary tangles in the hippocampal and cortical regions were significantly increased in diabetic patients carrying the APOEε4 allele compared to normal subjects.
Luchsinger et al4 studied the association between vascular risk factors (including diabetes, hypertension, heart disease, and smoking) and AD in 1,138 elderly subjects with a mean age of 76.2 years and a mean follow-up of 5.5 years and found that diabetes was the strongest association among these risk factors with an RR of 4.4. In addition, a recent meta-analysis also came to similar conclusions. In addition, a recent meta-analysis reached similar conclusions. This study included 28 cohort studies of the association between AD and diabetes, including 89,708 diabetic patients and 1,058,333 non-diabetic patients, with follow-up ranging from 2 to 30 years, and concluded that diabetes increased the incidence of AD (RR=1.56).5 Thus, diabetes may be the next major risk factor for AD after age, sex, and education level. after age, gender, and education level. However, it is promising that this factor may be controllable and provides new ideas for the treatment of AD as well.
The common pathogenesis of AD and T2DM – insulin resistance and impaired insulin signaling
Current research suggests that insulin resistance in AD brain is closely related to its biomarker Aβ. Soluble Aβ oligomers are able to bind to the cell membrane of neurons, causing a decrease in the transfer and number of insulin receptors indicated by the cell membrane.6 This is consistent with the findings of neuropathological studies in AD patients.7 Suzanne et al.7 performed autopsies on 45 AD patients and found that the number of insulin receptors in the brains of AD patients was decreased by 80% compared to normal subjects, and the ability of insulin to bind to the receptors was also decreased. The ability of insulin to bind to the receptors was also decreased.
Further results from animal experiments also found that insulin, insulin-like growth factor, and the corresponding mRNA, IR, were reduced in the brains of mice in the AD model compared to normal mice.8 Insulin resistance, the reduced number of insulin receptors and the reduced binding capacity lead to impaired insulin-related signaling. There are at least two known insulin signaling pathways: one is through insulin receptor substrate (IRS) activation of phosphoinositide 3-kinase (PI-3K); the other is through GRB2/SOS and RAS protein activation with mitogen activated protein kinase (MAPK).
When PI-3K signaling is impaired in the brain of AD patients, it leads to an increase in glycogen synthase kinase 3α (GSK3α) activity on the one hand, and experiments have shown that increased GSK3α activity can increase the activity of γ-secretase, leading to an increase in Aβ synthesis.9 Thus, a vicious cycle will be formed between insulin resistance and Aβ deposition, and to a certain extent, the more severe insulin resistance is, the more Aβ formation will occur. The more severe the insulin resistance, the more Aβ formation, and the more Aβ deposition will aggravate the insulin resistance.
On the other hand, impaired PI-3K signaling also leads to increased activity of GSK-3β, an important kinase involved in tau protein hyperphosphorylation.10 In T2DM, TNF-α activates c-Jun N-terminal kinase (JNK), which leads to phosphorylation of the insulin receptor substrate serine, ultimately leading to insulin resistance. Similarly, in hippocampal neuronal experiments, Aβ monomers can activate the TNF-α/JNK transmission pathway, leading to insulin resistance.8 In conclusion, insulin resistance plays an important role in the pathogenesis of AD and is therefore also considered as “diabetic encephalopathy” or “metabolic disorder encephalopathy”. Diabetic encephalopathy” or “metabolic disorder encephalopathy”, also known as “type 3 diabetes “11.
Insulin in the brain is mainly of peripheral origin, but insulin deficiency and insulin resistance are still present in the brain of AD patients with high peripheral insulin levels. This may be related to the role of insulin degrading enzyme (IDE) with insulin and Aβ. IDE secreted by astrocytes is capable of degrading both insulin and Aβ, but with higher specificity for insulin. Hyperinsulinemia often occurs early in diabetic patients, and insulin easily crosses the blood-brain barrier leading to excessively elevated insulin levels in the brain. The over-activated IDE causes insulin to be over-degraded, resulting in insulin deficiency in the brain; at the same time, the IDE is heavily depleted in the process of insulin degradation, as well as its own higher binding power to insulin, resulting in insufficient degradation of Aβ by the IDE, making A β deposition in the brain; Aβ deposition in the brain can destroy insulin receptors and impair insulin signaling pathways, making the brain insulin deficiency in AD patients accompanied by insulin resistance13.
Clinical studies on the use of glucose-lowering drugs for AD treatment
There are no effective drugs for the treatment of AD. The available drugs for AD treatment can only delay the progression of AD patients for 6-12 months and are only 50% effective.14 In contrast to the lack of treatment, the number of AD patients is large and increasing, with about 35 million AD patients worldwide and in 40 years, the number will reach more than 100 million.15 Therefore, it is important to identify drugs that can effectively treat AD as early as possible. Therefore, it is important to identify drugs that can effectively treat AD as early as possible. Based on the above findings that insulin deficiency, insulin resistance, and impaired insulin signaling exist in the brain of AD patients, increasing insulin levels and promoting insulin-related signaling would be new targets for the treatment of AD. The following paper focuses on clinical studies of insulin, thiazolidinediones and glucagon-like peptide-1 (GLP-1) analogues in the treatment of AD.
Intranasal insulin administration
Intranasal insulin administration not only has no risk of hypoglycemia compared with intravenous or subcutaneous insulin injection, but also allows insulin to bypass the blood-brain barrier and pass rapidly and efficiently through the blood vessels and axons around the olfactory and trigeminal nerves into the skull.16 Therefore, intranasal insulin administration may be an effective route for long-term treatment of patients with AD.
Reger et al17 found that cognitive functions such as memory, verbal skills and attention were improved in subjects with AD and mild cognitive dysfunction after 21 days of intranasal insulin administration of 20 IU twice daily. Subsequently, Craft et al18 investigated the effects of insulin on cognitive function, brain glucose metabolism levels, and intracranial biomarkers associated with AD in AD patients.
The results found that insulin improved cognitive function in the subjects, and these patients with improved cognitive function had reduced levels of Aβ42 and tau protein/ Aβ42 ratio. The researchers also combined positron emission tomography and showed that insulin increased metabolic levels in the temporoparietal, frontal, and cuneate regions of the brain, indicating enhanced brain function in these regions.Reger et al.19 further investigated the effect of the APOEε4 gene on insulin treatment and found that only non-APOEε4 carriers were able to benefit from insulin treatment.
Since the current clinical studies on the use of insulin for the treatment of AD patients still have problems such as small sample size and short treatment time, no conclusive conclusion can be made about the therapeutic effect of insulin on AD patients. More clinical trials with larger sample sizes and longer durations are needed to determine the effectiveness of insulin in the treatment of AD.
Metformin
Metformin is an oral metformin drug that can lower glucose by inhibiting hepatic glycogen output, increasing insulin sensitivity, and inhibiting gluconeogenesis. Metformin is also anti-inflammatory, anti-thrombotic, and reduces the risk of diabetes and metabolic syndrome in non-diabetic patients. It is worth mentioning that long-term use of metformin also reduces the risk of prostate and other cancers in patients37.
Studies have shown that patients with combined T2DM and AD have a faster rate of cognitive decline with metformin than those without metformin.38 This study suggests that metformin has neuroprotective effects through certain pathways. A large 8-year epidemiological study showed that metformin and sulfonylureas reduced the risk of AD in patients with diabetes by 38%.39 However, a recent large UK study of the effect of metformin and other glucose-lowering drugs on the development of AD in patients with T2DM, which included 7,086 patients with AD and the same number of patients without dementia, showed that metformin increased the risk of AD in patients with T2DM. More clinical trials are needed to validate these conflicting results40.
Thiazolidinediones (TZDs)
TZDs are peroxisome proliferator-activated receptor-γ (PPARγ) agonists, which are capable of lowering glucose by activating PPARγ and increasing the body’s sensitivity to insulin.20 In addition to its glucose-lowering effects, TZD is also a powerful anti-inflammatory agent.21 Considering the role of inflammatory response in T2D22 and AD23 , it may also play a role in reducing AD. , it may also play a role in reducing the risk of developing AD.
Pioglitazone and rosiglitazone are two of its representative drugs. In a small sample size trial on the effect of rosiglitazone on cognitive function, 30 subjects with AD and mild cognitive dysfunction were randomized to a placebo group and an experimental group of 4 mg rosiglitazone, and the treatment effect was examined after 6 months of treatment. It was found that the experimental group had significantly lower fasting plasma insulin levels and improved memory and selective attention compared to the control group, but Aβ levels were not changed, presumably rosiglitazone may indirectly affect central cognitive function by reducing peripheral insulin levels24.
Next, a large clinical trial including 511 subjects with mild to moderate AD regarding the effect of rosiglitazone on cognitive function found that the effect of rosiglitazone on cognitive function in AD patients was associated with APOE-ε4 genotype, with significant improvement in cognitive function in APOE-ε4-negative subjects but not in APOE-ε4-positive subjects taking 8 mg rosiglitazone, and in subjects in the low-dose rosiglitazone experimental group also showed diminished cognitive function25.
However, a larger phase III trial examining the effects of rosiglitazone on cognitive function in AD patients found that even APOE-ε4-negative subjects did not benefit from rosiglitazone treatment, regardless of dose.26 Rosiglitazone has even been reported to cause cognitive decline in some diabetic patients.27 There are limited clinical trials on the use of pioglitazone for AD treatment. However, the results of the available studies are similar to those of rosiglitazone, with some studies reporting benefit and others reporting no benefit28.
The main reason for limiting the clinical use of TZDs compared to their efficacy is that they cause edema and congestive heart failure, and rosiglitazone has been partially or completely restricted for the treatment of T2DM in the United States and Europe due to its increased risk of heart attack and stroke.29 The use of rosiglitazone for the treatment of AD is also not recommended.28 In conclusion, there is still a long way to go before TZDs are used in the clinical treatment of AD. to go.
Glucagon-like peptide-1 (GLP-1) analogs
GLP-1 is an enteric-derived glucagon-producing hormone that lowers blood glucose by increasing insulin secretion and inhibiting glucose uptake.30 GLP-1 analogs, exenatide and liraglutide, are currently used in the clinical treatment of T2DM. 31, based on the fact that reduced insulin receptors play an important role in the development of AD, GLP-1 analogs may be a good choice for the treatment of AD.
More importantly, the ability of GLP-1 analogs to effectively cross the blood-brain barrier into the brain 32 further enhances their value for clinical application. Although a large number of basic studies have shown that GLP-1 analogs have anti-inflammatory33, neurological and synaptic protective effects34, and most importantly, also reduce intracranial Aβ deposition35 and protect neurons from Aβ-induced neurological damage.36 However, there is a lack of relevant clinical study data.
However, there are two large clinical trials to look forward to, one hosted by the National Institutes of Health and the National Institute on Aging to study the effects of exenatide on cognitive function, brain metabolic levels, and biomarkers such as Aβ. The trial includes 230 patients with mild cognitive impairment and mild AD and will last up to 3 years. Another ongoing 1-year phase II clinical trial in the UK to study the effects of liraglutide on brain metabolic levels, inflammatory markers and levels of tau protein and Aβ is enrolling 206 patients with mild cognitive impairment.