Alzheimer's & Diabetes

See also



A study involving older adults has found that diabetes was associated with higher levels of tau protein and greater brain atrophy.

The study involved 816 older adults (average age 74), of whom 397 had mild cognitive impairment, 191 had Alzheimer's disease, and 228 people had no cognitive problems. Fifteen percent (124) had diabetes.

Those with diabetes had greater levels of tau protein in the spinal and brain fluid regardless of cognitive status. Tau tangles are characteristic of Alzheimer's.

Those with diabetes also had cortical tissue that was an average of 0.03 millimeter less than those who didn't have diabetes, regardless of their cognitive status. This greater brain atrophy in the frontal and parietal cortices may be partly related to the increase in tau protein.

There was no link between diabetes and amyloid-beta, the other main pathological characteristic of Alzheimer's.

Previous research has indicated that people with type 2 diabetes have double the risk of developing dementia. Previous research has also found that those who had been diabetic for longer had a greater degree of brain atrophy

The findings support the idea that type 2 diabetes may have a negative effect on cognition independent of dementia, and that this effect may be driven by an increase in tau phosphorylation.

A long-running study comparing African-Americans and Nigerians has found the incidence of dementia has fallen significantly over two decades among the African-Americans, but remained the same for the Nigerians (for whom it was lower anyway).

The study enrolled two cohorts, one in 1992 and one in 2001, who were evaluated every 2–3 years until 2009. The 1992 cohort included 1440 older African-Americans (70+) and 1774 Nigerian Yoruba; the 2001 cohort included 1835 African-Americans and 1895 Yoruba. None of the participants had dementia at study beginning.

The overall standardized annual incidence rate was 3.6% for the 1992 African-American cohort, and 1.4% for the 2001 cohort. For the Yoruba, it was 1.7% and 1.4%, respectively.

It's suggested that one reason for the improvement among African-Americans may be medications for cardiovascular conditions. Although both groups had similar rates of high blood pressure, this was recognized and treated in the American group but not in the Nigerian.

As you can see, African-Americans in the earlier cohort were more than twice as likely as Africans to develop dementia. Their decrease has brought them into line with the African rate.

Although the rate of new cases of dementia decreased, the African-Americans enrolling in 2001 had significantly higher rates of diabetes, hypertension and stroke, but also higher treatment rates, than the African-Americans who enrolled in 1992.

The finding offers hope that treatment can offset the expected increase in dementia resulting from the rise in lifestyle diseases.

A large meta-analysis has concluded that having diabetes increases the chance that a person with mild cognitive impairment will progress to dementia by 65%.

There was no consistent evidence that hypertension or cholesterol levels increased the risk of someone with MCI progressing to dementia. Smoking was similarly not associated with increased risk, although the reason for this probably lies in mortality: smokers tend to die before developing dementia.

There was some evidence that having symptoms of psychiatric conditions, including depression, increased the risk of progressing to dementia.

There was some evidence that following a Mediterranean diet decreased the risk of an individual with amnestic MCI progressing to Alzheimer's, and that higher folate levels decrease the risk of progressing from MCI to dementia. The evidence regarding homocysteine levels was inconsistent.

The evidence indicates that level of education does not affect the risk of someone with MCI progressing to dementia.

Do note that all this is solely about progression from MCI to dementia, not about overall risk of developing dementia. Risk factors are complex. For example, cholesterol levels in mid-life are associated with the later development of dementia, but cholesterol levels later in life are not. This is consistent with cholesterol levels not predicting progression from MCI to dementia. Level of education is a known risk factor for dementia, but it acts by masking the damage in the brain, not preventing it. It is not surprising, therefore, that it doesn't affect progression from MCI to dementia, because higher education helps delay the start, it doesn't slow the rate of decline.

Do note also that a meta-analysis is only as good as the studies it's reviewing! Some factors couldn't be investigated because they haven't been sufficiently studied in this particular population (those with MCI).

The long-running Cache County study has previously found that 46% of those with MCI progressed to dementia within three years; this compared with 3% of those (age-matched) with no cognitive impairment at the beginning of the study.

More recently, data from the long-running, population-based Rotterdam study revealed that those diagnosed with MCI were four times more likely to develop dementia, over seven years. compared with those without MCI. Of those with MCI (10% of the 4,198 study participants), 40% had amnestic MCI — the form of MCI that is more closely associated with Alzheimer's disease.

The 2014 study also found that older age, positive APOE-ɛ4 status, low total cholesterol levels, and stroke, were all risk factors for MCI. Having the APOE-ɛ4 genotype and smoking were related only to amnestic MCI. Waist circumference, hypertension, and diabetes were not significantly associated with MCI. This may be related to medical treatment — research has suggested that hypertension and diabetes may be significant risk factors only when untreated or managed poorly.

[3913] Cooper, C., Sommerlad A., Lyketsos C. G., & Livingston G.
(2015).  Modifiable Predictors of Dementia in Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.
American Journal of Psychiatry. 172(4), 323 - 334.

[3914] Tschanz, J. T., Welsh-Bohmer K. A., Lyketsos C. G., Corcoran C., Green R. C., Hayden K., et al.
(2006).  Conversion to dementia from mild cognitive disorder The Cache County Study.
Neurology. 67(2), 229 - 234.

de Bruijn, R.F.A.G. et al. Determinants, MRI Correlates, and Prognosis of Mild Cognitive Impairment: The Rotterdam Study. Journal of Alzheimer’s Disease, Volume 42/Supplement 3 (August 2014): 2013 International Congress on Vascular Dementia (Guest Editor: Amos D. Korczyn), DOI: 10.3233/JAD-132558.

Glucose levels linked to cognitive decline in those with MCI

A study involving 264 older adults with mild cognitive impairment has found that those with normal glucose levels (167; 63%) had less cognitive decline over 2 years than those with impaired (high) glucose levels (97; 37%). They also showed less brain shrinkage and were less likely to develop Alzheimer’s. The fasting glucose levels were classified according to the American Diabetes criteria.

[3614] Vos, S JB., Xiong C., Visser P J., Jasielec M. S., Hassenstab J., Grant E. A., et al.
(2013).  Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study.
The Lancet Neurology. 12(10), 957 - 965.

Rat study suggests cognitive decline in diabetics related to amyloid-beta buildup

A rat study supports the growing evidence of a link between type 2 diabetes and Alzheimer’s. In this study, 20 rats were fed a high-fat diet to give them type 2 diabetes. A subsequent test found that the diabetic rats had significantly poorer memories than the control group of rats on a healthy diet (the rats were taught to associate a dark cage with an electric shock; how long the rat continues to remember that the stimulus means a shock — as shown by their frozen reaction — is taken as a measure of how good their memory is; the diabetic rats froze for less than half the time of the controls).

The diabetic rats then had their brains (specifically, the hippocampus) injected with antibodies that disrupt amyloid-beta plaques. This produced no change in their behavior. However, when they were given antibodies that disrupt amyloid-beta oligomers (precursors of the plaques), the memory deficit was reversed, and they behaved the same as the healthy rats.

These findings suggest that the cognitive decline often seen in type 2 diabetes is not due to the disruption in insulin signaling, as thought, but rather the build-up of amyloid oligomers. Previous research has shown that the same enzymes break down both insulin and the oligomers, so when there’s a lot of insulin (which the enzymes prioritize), the enzymes don’t have as much opportunity to work on breaking down the oligomers. The oligomers collect, preventing the insulin from reaching their proper receptors in the hippocampus, which impairs cognitive function.

All this supports the idea that type 2 diabetes may be thought of as early-stage Alzheimer's. Obviously a lot more work needs to be done to confirm this picture, but certainly in the mean time, it can be taken as another reason to take type 2 diabetes very seriously.

McNay, E.C., Osborne, D., et al. 2014. Preliminary data presented at the Society for Neuroscience meeting in San Diego in November, 2013

High blood sugar makes Alzheimer’s plaque more toxic

A study of cell cultures taken from rodents’ cerebral blood vessels has found that, while cells exposed to either high glucose or amyloid-beta showed no changes in viability, exposure to both decreased cell viability by 40%. Moreover, cells from diabetic mice were more vulnerable to amyloid-beta, even at normal glucose levels.

The findings support evidence pointing to high glucose as a risk factor for vascular damage associated with Alzheimer’s, and adds weight to the view that controlling blood sugar levels is vital for those with diabetes.

[3558] Carvalho, C., Katz P. S., Dutta S., Katakam P. V. G., Moreira P. I., & Busija D. W.
(2014).  Increased Susceptibility to Amyloid-β Toxicity in Rat Brain Microvascular Endothelial Cells under Hyperglycemic Conditions.
Journal of Alzheimer's Disease. 38(1), 75 - 83.

Mechanism by which diabetes increases Alzheimer's risk revealed

Although it's well-established now that diabetes is a major risk factor for dementia, the reason is still not well understood. To test the hypothesis that epigenetic changes in the brain, affecting synaptic function, may be part of the reason, the brains of diabetics and others were examined post-mortem. Diabetics' brains were found to have significantly higher expression of a class of molecules (histone deacetylases class IIa) and this was associated with impaired expression of synaptic proteins.

This finding was confirmed in mice genetically engineered to develop an Alzheimer’s-type condition, who were induced to develop diabetes. The increase of HDAC IIa was associated with synaptic impairments in the hippocampus, through the work of amyloid oligomers.

Some 60% of Alzheimer's patients have at least one serious medical condition associated with diabetes.

[3615] Wang, J., Gong B., Zhao W., Tang C., Varghese M., Nguyen T., et al.
(2014).  Epigenetic Mechanisms Linking Diabetes and Synaptic Impairments.
Diabetes. 63(2), 645 - 654.

High Blood Sugar Linked to Dementia

A seven-year study involving 2,067 older adults (average age 76 at start) has found that those with a high blood glucose level, whether or not they had diabetes, were more likely to develop dementia. Moreover, this was a linear relationship — meaning that the risk steadily increased with higher glucose levels, and decreased the lower it was. Thus, even those with ‘normal’ glucose levels were subject to this relationship, with those whose blood sugar averaged 115 milligrams per deciliter, having an 18% higher risk of dementia than those at 100 mg/dL. Other risk factors, such as high blood pressure, smoking, exercise, and education, were taken into account in the analysis.

The findings add weight to the idea that the brain is a target organ for damage by high blood sugar.

Over the course of the study, a quarter (524) developed dementia of some kind, primarily Alzheimer’s disease or vascular dementia. At the beginning of the study, 232 (11%) had diabetes, and a further 111 developed it by the end of the study. Nearly a third (32%) of those with diabetes at the beginning of the study developed dementia, compared to just under a quarter of those without (24.5%).

The journal article is freely available at

[3563] Crane, P. K., Walker R., Hubbard R. A., Li G., Nathan D. M., Zheng H., et al.
(2013).  Glucose Levels and Risk of Dementia.
New England Journal of Medicine. 369(6), 540 - 548.

Undiagnosed pre-diabetes highly prevalent in early Alzheimer's disease

A study involving 128 patients with mild to moderate Alzheimer’s disease, which had specifically excluded those with known diabetes, found that 13% of them did in fact have diabetes, and a further 30% showed glucose intolerance, a pre-diabetic condition.

Turner presented his findings at the Alzheimer's Association International Congress in Boston on July 14.

Association between hypoglycemia, dementia in older adults with diabetes

A 12-year study involving 783 older adults with diabetes (average age 74) has found that 148 (19%) developed dementia. Those 61 patients (8%) who had a reported hypoglycemic event were twice as likely to develop dementia compared to those who didn’t suffer such an event (34% vs. 17%). Similarly, those with dementia were more likely to experience a severe hypoglycemic event.

The findings suggest some patients risk entering a downward spiral in which hypoglycemia and cognitive impairment fuel one another, leading to worse health

[3622] Yaffe, K., CM F., N H., & et al
(2013).  ASsociation between hypoglycemia and dementia in a biracial cohort of older adults with diabetes mellitus.
JAMA Internal Medicine. 173(14), 1300 - 1306.

Dementia risk greatest for older Native-Americans and African-Americans with diabetes

In the first study to look at racial and ethnic differences in dementia risk among older adults with type 2 diabetes, Native Americans were 64% more likely to develop dementia than Asian-Americans, and African-Americans were 44% more likely. Asian-Americans had the lowest risk, and non-Hispanic whites and Latinos were intermediate.

The study involved 22,171 older adults (60+), of whom 3,796 patients (17%) developed dementia over the 10 years of the study. Almost 20% of the African-Americans and Native Americans developed dementia.

The ethnic differences were not explained by diabetes-related complications, glycemic control or duration of diabetes, or neighborhood deprivation index, body mass index, or hypertension.

[3590] Mayeda, E. R., Karter A. J., Huang E. S., Moffet H. H., Haan M. N., & Whitmer R. A.
(2014).  Racial/Ethnic Differences in Dementia Risk Among Older Type 2 Diabetic Patients: The Diabetes and Aging Study.
Diabetes Care. 37(4), 1009 - 1015.

I’ve talked before about the evidence linking diabetes to an increased risk of Alzheimer’s disease, but now a new study suggests that elevated blood sugar levels increase Alzheimer’s risk even in those without diabetes, even in those without ‘pre-diabetes’.

The study used data from 124 cognitively normal, non-diabetic adults (aged 47-68) with a family history of Alzheimer’s disease. Higher faster serum glucose levels were associated with lower rates of metabolism in brain regions associated with reduced metabolism in Alzheimer’s. This link was not affected by the presence or otherwise of the so-called ‘Alzheimer’s gene’ (ApoE4).

The finding raises additional questions about the role of the metabolic process in the development of Alzheimer’s.

[3403] Burns, C. M., Chen K., Kaszniak A. W., Lee W., Alexander G. E., Bandy D., et al.
(2013).  Higher serum glucose levels are associated with cerebral hypometabolism in Alzheimer regions.
Neurology. 80(17), 1557 - 1564.

A study following 837 people with MCI, of whom 414 (49.5%) had at least one vascular risk factor, has found that those with risk factors such as high blood pressure, diabetes, cerebrovascular disease and high cholesterol were twice as likely to develop Alzheimer's disease. Over five years, 52% of those with risk factors developed Alzheimer's, compared to 36% of those with no risk factors In total, 298 people (35.6%) developed Alzheimer's.

However, of those with vascular risk factors, those receiving full treatment for their vascular problems were 39% less likely to develop Alzheimer's disease than those receiving no treatment, and those receiving some treatments were 26% less likely to develop the disease.

Treatment of risk factors included using high blood pressure medicines, insulin, cholesterol-lowering drugs and diet control. Smoking and drinking were considered treated if the person stopped smoking or drinking at the start of the study.

It’s been suggested before that Down syndrome and Alzheimer's are connected. Similarly, there has been evidence for connections between diabetes and Alzheimer’s, and cardiovascular disease and Alzheimer’s. Now new evidence shows that all of these share a common disease mechanism. According to animal and cell-culture studies, it seems all Alzheimer's disease patients harbor some cells with three copies of chromosome 21, known as trisomy 21, instead of the usual two. Trisomy 21 is characteristic of all the cells in people with Down syndrome. By age 30 to 40, all people with Down syndrome develop the same brain pathology seen in Alzheimer's. It now appears that amyloid protein is interfering with the microtubule transport system inside cells, essentially creating holes in the roads that move everything, including chromosomes, around inside the cells. Incorrect transportation of chromosomes when cells divide produces new cells with the wrong number of chromosomes and an abnormal assortment of genes. The beta amyloid gene is on chromosome 21; thus, having three copies produces extra beta amyloid. The damage to the microtubule network also interferes with the receptor needed to pull low-density lipoprotein (LDL — the ‘bad’ cholesterol) out of circulation, thus (probably) allowing bad cholesterol to build up (note that the ‘Alzheimer’s gene’ governs the low-density lipoprotein receptor). It is also likely that insulin receptors are unable to function properly, leading to diabetes.

Both diabetes and clinical depression are known to be risk factors for dementia. Now a study that tracked nearly 4000 diabetics over 5 years has found having both increased the risk 2.7-fold. Nearly 8% of the diabetics with major depression (36 of 455) developed dementia over the five years, compared to 4.8% of those with diabetes alone (163 of 3382). Those who developed dementia within 2 years of being diagnosed with depression were excluded. Depression is common among people who have diabetes.


Does diabetes speed up memory loss in Alzheimer's disease?

A four-year study involving 608 people with mild to moderate Alzheimer's disease, of whom just over 10% (63) had diabetes, has unexpectedly found that memory loss in those without diabetes declined faster than those with diabetes. The researchers speculate that elderly people with diabetes may be more likely to be taking cardiovascular medications (although having vascular factors was controlled for), or there may be some differences in the brain pathology of Alzheimer’s with diabetes compared to Alzheimer’s without diabetes.

Sanz, C., Andrieu, S., Sinclair, A., Hanaire, H., Vellas, B., & For the REAL.FR Study Group. (2009). Diabetes is associated with a slower rate of cognitive decline in Alzheimer disease. Neurology, 73(17), 1359-1366. doi: 10.1212/WNL.0b013e3181bd80e9.

Diabetes, high blood pressure may cause Alzheimer's sufferers to die sooner

A study involving 323 people who had no memory problems when first tested but later developed dementia has found that, after an Alzheimer’s diagnosis, people with diabetes were twice as likely to die sooner than those without diabetes, while those with high blood pressure were two-and-a-half times more like to die sooner than those with normal blood pressure. The average lifespan of a person diagnosed with Alzheimer's is three to nine years.

Helzner, E.P. et al. 2008. Survival in Alzheimer disease: A multiethnic, population-based study of incident cases. Neurology, 71, 1489-1495.

Diabetes in mid-life linked to increased risk of Alzheimer's disease

A large Swedish study involved over 2000 men has found that those with low insulin secretion capacity at age 50 were nearly one-and-a-half times more likely to develop Alzheimer’s disease than people without insulin problems. The risk remained significant regardless of blood pressure, cholesterol, body mass index and education, and was strongest in people who did not have the APOE4 gene.

Rönnemaa, E. et al. 2008. Impaired insulin secretion increases the risk of Alzheimer disease. Neurology, first published on April 9 as doi: doi:10.1212/01.wnl.0000310646.32212.3a

Significant dementia risk attributable to small blood vessel damage


The findings were reported at the annual meeting of the American Society for Biochemistry and Molecular Biology, April 5-9, San Diego.

Link between diabetes and Alzheimer's disease

A mouse study has shed light on the connection between diabetes and Alzheimer’s. It appears that the elevated blood glucose levels characteristic of diabetes interacts with beta amyloid in a way damaging to blood vessels in the brain.

Burdo, J.R. et al. 2008. The pathological interaction between diabetes and presymptomatic Alzheimer's disease. Neurobiology of Aging, Available online 26 March 2008

Support for view of Alzheimer's as form of diabetes

Research in the last few years has raised the possibility that Alzheimer’s memory loss could be due to a third form of diabetes. A new study clarifies the connection between insulin and Alzheimer’s. It seems that the toxic protein ADDL, found in the brains of individuals with Alzheimer’s, removes insulin receptors from nerve cells, rendering those neurons insulin resistant. The findings suggest that some existing drugs now used to treat diabetic patients may be useful for Alzheimer’s treatment.

Zhao,W-Q. et al. 2007. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB Journal, published online ahead of print August 24.

Diabetes associated with increased risk of mild cognitive impairment

A study involving 918 individuals older than 65 years (average age 75.9) who did not have mild cognitive disorder or dementia when they enrolled has found that, over some 6 years, diabetes was related to a significantly higher risk of developing amnestic mild cognitive impairment, after controlling for other risk factors. The results support other findings that type 2 diabetes mellitus increases the risk of Alzheimer's.

Luchsinger, J.A. et al. 2007. Relation of Diabetes to Mild Cognitive Impairment. Archives of Neurology, 64, 570-575.

High blood sugar linked to MCI and dementia

The first study to investigate the association over time between blood sugar and the risk of cognitive difficulties involved 1,983 post-menopausal women (mean age 67 years) and found that each 1% increase in their glycosylated hemoglobin level at the start of the four-year study period was associated with a 40% increased risk of developing MCI or dementia four years later. The glycosylated hemoglobin test gives a more stable measure of blood sugar level than the standard test, which measures blood sugar it the time of testing. A result of 7% or less indicates good long-term blood sugar control. Those with a level of 7% or more were four times more likely to develop MCI or dementia than women who tested at less than 7%.

Yaffe, K. et al. 2006. Glycosylated Hemoglobin Level and Development of Mild Cognitive Impairment or Dementia in Older Women. Journal of Nutrition, Health, and Aging, 10 (4)

Reduced insulin in the brain triggers Alzheimer's degeneration

By depleting insulin and its related proteins in the brain, researchers have replicated the progression of Alzheimer's disease – including plaque deposits, neurofibrillary tangles, impaired cognitive functioning, cell loss and overall brain deterioration – in an experimental animal model. Brain deterioration was not related to the pancreas, raising the possibility that Alzheimer's is a neuroendocrine disorder, or a Type 3 diabetes.

Lester-Coll, N. et al. 2006. Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer’s disease. Journal of Alzheimer’s Disease, 9(1)

Link between insulin and Alzheimer's

A new study has found that insulin and its related proteins are produced in the brain as well as the pancreas, and that reduced levels of these contribute to the degeneration of brain cells, an early symptom of Alzheimer's disease. The finding raises the possibility of a Type 3 diabetes.

de la Monte, S.M. & Wands, J.R. 2005. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: Relevance to Alzheimer's disease Journal of Alzheimer's Disease, 7(1), 45-61.

Diabetics at significantly higher risk for Alzheimer's disease

New findings from the Religious Orders Study add to research suggesting a link between diabetes mellitus and an increased risk of developing Alzheimer's disease. Some aspects of cognitive function appear to be affected differently than others, in particular perceptual speed declined significantly faster in those with diabetes.

[1296] Arvanitakis, Z., Wilson R. S., Bienias J. L., Evans D. A., & Bennett D. A.
(2004).  Diabetes Mellitus and Risk of Alzheimer Disease and Decline in Cognitive Function.
Arch Neurol. 61(5), 661 - 666.

Insulin-degrading enzyme may affect risk of Alzheimer’s disease

A new mouse study suggests that low levels of insulysin, an enzyme that degrades insulin, could increase the risk for Alzheimer's, and points to a new mechanism linking diseases like diabetes and Alzheimer's — the competition of multiple substrates, such as insulin and amyloid-beta, for a limiting amount of the insulysin enzyme. The insulysin enzyme, it seems, also degrades amyloid-beta peptides, and even a partial decrease in insulysin activity was found to raise amyloid-beta peptide levels in the brain.

[2406] Miller, B. C., Eckman E. A., Sambamurti K., Dobbs N., Chow M. K., Eckman C. B., et al.
(2003).  Amyloid-β peptide levels in brain are inversely correlated with insulysin activity levels in vivo.
Proceedings of the National Academy of Sciences. 100(10), 6221 - 6226.

Poorly controlled diabetes could lead to dementia in the elderly

It now appears that the reason why diabetic people age 60 and older tend to perform more poorly on cognitive tests is because of improper management of their disease. A recent study evaluated the association between diabetes mellitus status and cognitive function in 2,583 adults aged 60 and older, grouping participants according to their diabetic status (poorly controlled diabetes; adequately controlled diabetes; those with impaired glucose tolerance; and a non-diabetic control group). Cognitive ability was measured by a series of simple memory questions. Only those with poorly controlled diabetes performed poorly on the cognitive test.

The researchers presented their findings in April at the American Academy of Neurology conference in Honolulu.