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Type 3 diabetes (i.e., T3D) has often been suggested to be an alternate name for Alzheimer's disease (i.e., AD). AD accounts for 60% to 80% of all dementias. It currently afflicts 55 million individuals and is expected to afflict 139 million by the year 2050. Type 2 diabetes (T2D), also known as adult-onset diabetes, is a disease in which the peripheral tissues of individuals are insulin resistant and their β-pancreatic cells are functionally impaired. It afflicts about 10% of the world's population and is suggested to be the cause for some cases of AD.[1][2][3] There are two forms of AD. Early onset AD (i.e., EOAD) generally afflicts individuals between 45 to 65 years of age and accounts for 5% to 6% of all AD cases. About 10-20 % of all EOAD cases are due to inheriting a defective gene (see Early onset AD). The remaining cases of EOAD is associated with various risk factors such as head injuries, cardiovascular diseases, chronic schizophrenia, the Down syndrome, and lifestyle features such as poor diets, smoking, alcohol use, and sedentary lifestyles.[3][4] The other form of AD is termed Late onset AD (i.e., LOAD). LOAD is typically diagnosed in individuals more than 64 years old. It is the form of AD associated with T2D: LOAD is almost twice as common in individuals who have T2D. A study done in the USA found that there were 71,550 deaths between 1999 and 2019 among individuals who had both LOAD and T2D. Because the brain tissues of individuals with LOAD are abnormally resistant to insulin's stimulation of neuron functions, some studies have termed LOAD in individuals with T2D as "T3D". This is based on the idea that T2D causes LOAD.[1][5][6][7] Overall, the etiology of LOAD involves neuroinflammation, i.e., it is thought to be caused by a) inflammation in certain areas of the brain; 2) the formation of excessive phospholatiions of certain neuronal proteins such as the Tau protein); and 3) the accumulation of plaques (i.e., misfolded and clumped protein fragments of amyloid beta (i.e., Aβ)). Ultimately the formation of these and other proteins can cause dysfunction of brain neurons.[3] AD must be distinguished from the second most common form of dementia, vascular dementia (i.e., VD). VD is caused by vascular events such as stroke, atherosclerosis, and various cardiovascular diseases. Pure VD represents about 15% of all dementia cases.[8][9] Another definition of dementia is termed Alzheimer's disease-related dementia (i.e., ADRD). It consists of 3 different types: vascular dementia (i.e., VA, as just described); Lewy body dementia which is subclassed as dementia with Lewy bodies and Parkinson's disease dementia, and frontotemporal dementia.[10]
Studies examining the role of T2D in causing AD
Genetic studies
A study of 500 patients with Parkinson's disease dementia, 400 patients with AD, and 500 with neither disease examined 32 genetic variantss in their CDC123, CDKAL1, CDKN2B, FTO, GLIS3, HHEX, IGF2BP2, KCNJ11, KCNQ1, SLC30A8, and TCF7L2 genes. The study did not find any significant associations between these variants with the risk of developing or the severity of the cognitive impairments in patients with Parkinson's disease or AD.[11] A more recent study examined the associations between polygenic risk scores, i.e. PLCs for T2D in 29,139 adults (mean age 55) followed for 20–23 years. The study found higher PLCs were associated with the development of VA but not AD.[12] Another study examined the regions based on results of recent genome-wide association studies (GWAS) in T2D study tested associations between polygenic risk scores, i.e. PLCs for T2D in 29 139 adults (mean age 55) followed for 20–23 years. The study found higher PLCs were associated with the development of VA but not AD.[12] A third study of 33,136 idividuals (mean age 72.5 years old) from southern China compared the PLCs of individuals with various forms of non-T2D dementia to individuals with T2D. It examined the closeness of the genomic variants of individuals to that of individuals with a specific disease.(https://www.genome.gov/Health/Genomics-and-Medicine/Polygenic-risk-score) The study evaluated the closeness of the PLCs in individuals with various forms of dementia. It found a highly significant relationship between the PLCs in T2D to those with VD but not with AD or other forms of dementia.<https://www.genome.gov/Health/Genomics-and-Medicine/Polygenic-risk-scores. The study suggested that the genetic variants in Chinese individuals with T2D contribute to their development of VD but not AD or other forms of dementia.[13] Similar results occurred in a study which examined 658,582 veterans in the United States of America Department of Veterans Affairs in the enrolled in the Million Veteran Program (see Joel Kupersmith#Veterans Advocacy). Another study found that the genetic risk scores (i.e., specific genes or variations in genes that increase a person's chance of developing certain diseases) in individuals of European descent were related to VD but not AD. However, individuals of African or Hispanic descent showed no associations of these genes with any of the studied dementias.[14] Another study used Mendelian randomization methods to analyze 8 publications that included 88,905 up to 788,989 individuals all of whom were of European ancestry. Mendelian randomization uses the properties of genetic variations (usually single nucleotide polymorphisms) in germline cells. Finding that a set of genetic variants are associated with an outcome adds strength to the conclusion that the exposure has a causal effect on the outcome. This method is most commonly implemented using the instrumental variables estimation. The study found no evidence for a causal relationship between genetically predicted T2D and genetically predicted AD.[15][16]
We tested associations between polygenic risk scores for type 2 diabetes, fasting glucose, fasting insulin and haemoglobin A1c as exposure variables and dementia as outcome variables in 29 139 adults (mean age 55) followed for 20–23 years
T2D inhibitor studies
Pioglitazone is a PPAR-gamma agonist that is effective in treating T2D. Two phase III clinical trials evaluated the safety and efficacy of pioglitazone in treating mild cognitive impairments in patients with early-onset AD. Both trials were terminated because the drug did not show sufficient efficacy.[17][18] Another study examined the effects of various drugs used to treat T2D in 1,094,761 T2D patients that for the first-time were diagnosed with AD. The drugs included insulin, metformin (also termed Glucophage), dipeptidyl-peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors, sulfonylureas, thiazolidinediones, and GLP-1 receptor agonists (i.e., albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide). The study found that only one of these drugs, semaglutide: a) caused a lower risk of developing AD and b) significantly lower AD-related medication prescriptions in patients who developed AD. This study suggests that inhibiting T2D in general does not suppress AD, that the specific actions of semaglutide is not caused by its anti-AD actions, and supports future to determine the cause for semaglutide's ability to delay or slow down the onset of AD.[18] Semaglutide (also termed Ozempic, Rybelsus, and Wegovy) inhibits activation of the Glucagon-like peptide-1 receptor. It has been successfully used to inhibit the progression of Type 2 diabetes as well as to treat obesity, hypertension, and cardiovascular diseases. Studies have suggested that it may be useful for treating AD.[19][20] However, two randomized, double-blinded studies of 3808 adults aged 55-85 years-old with AD evaluated the efficacy and safety of oral semaglutide compared a placebo in treating AD. (The study's definition of AD included detection of certain amyloid proteins in the brain by positron emission tomography or cerebrospinal fluid). Adverse events during treatment were reported in 1,729 (i.e., 91.2%) of 1896 participants receiving semaglutide and 1613 (84.8%) of 1,902 receiving a placebo. There was one fatality in the semaglutide-treated and four fatalities in the placebo group. These results failed to support the conclusion that semaglutide reduced risk of AD.[21]https://www.biospace.com/press-releases/novo-nordisk-a-s-evoke-phase-3-trials-did-not-demonstrate-a-statistically-significant-reduction-in-alzheimers-disease-progression)
A study of 33,136 older (mean age 72.5 years old) individuals from southern China compared the polygenic risk scores, i.e. PLCs of individuals with various forms of dementia to individuals with T2D. PLCs is an individuals estimated genetic predisposition for a given trait. [13] That is, it examined the closeness of the genomic variants of test individuals to that of individuals with a specific disease.https://www.genome.gov/Health/Genomics-and-Medicine/Polygenic-risk-scores) The study tested the closeness of the PLCs in individuals with that in the T2D individuals with various forms of dementia. It found a highly significant relationship between the PLCs in T2D to those in vascular dementia but not in AD or other forms of dementia.<https://www.genome.gov/Health/Genomics-and-Medicine/Polygenic-risk-scores). The study suggested that the genetic variants in Chinese individuals with T2D contribute to their development of VD but nor AD nor other forms of dementia. One study of 658,582 veterans in the United States of America Department of Veterans Affairs in the Million Veteran Program (see Joel Kupersmith#Veterans Advocacy MVP.[13] Similar results occurred in two other studies. A study of [14]
A study examined 40 publications consisting of 7,076,724 individuals. It found that longer durations of diabetes and higher numbers of hypoglycemia episodes were significantly related to the development of various forms of dementia including AD, VD, and dementias caused by brain injuries or strokes. These findings suggest that it is not T2D per se but rather various forms of brain injuries that cause AD.[22]