Diabetes And Alzheimer DiseaseWhat Is The Link?

Mohamed KamarProfessor Of Diabetes And

EndocrinologyZagazig Faculty Of Medicine

Alzheimer’s disease and related dementias

• 5.2 million people with ADRD In the US in 2014• 16 million people with ADRD In the US in 2050• 1:3 of 65+ dies with ADRD, ~1:2 of 85+ dies with ADRD• 6th leading cause of death• $214 billion in the direct care costs

• Comparison– Cancer

• $ 86.6 billion direct care• $130 billion lost productivity

– Heart disease $106.9 billion direct care+lost productivity

• Research from NIH ADRD $550M Cancer $6B

WHAT IS ALZHEIMER’S DISEASE?

Amyloid Accretion 5–20 years before diagnosis of Alzheimer’s dementia

• Early, a protein fragment called amyloid-beta aggregates in the brain centers that form new memories.

• The amyloid buildup results in damage to synapses

• Amyloid blocks chemical signals (neurotransmitters) from reaching receptors on receiving neurons.

• Amyloid is a biomarker detected by the presence of plaques

• This buildup can be captured by various forms of neuroimaging, including positron-emission tomography (PET), that detect a radioactive compound, Pittsburgh imaging compound-B (PIB), able to bind specifically to amyloid.

• A spinal tap can also be used to gauge the amyloid biomarker

Amyloid deposition in synapses

TAU Buildup1–5 years before diagnosis

• Before symptoms would justify an Alzheimer’s diagnosis, a protein called tau inside neurons begins misbehaving.

• Normally tau helps to maintain the structure of tiny tubes (microtubules) critical to the proper functioning of neurons.

• But now phosphate groups begin to accumulate on tau proteins , which detach from the microtubules.

• The tubules go on to disintegrate, and tau then aggregates, forming tangles that interfere with cellular functions.

• A sample of spinal fluid can detect this process

TAU Buildup inside cells

1–3 years before diagnosis• As the underlying disease process advances,

nerve cells start to die, and patients and family notice memory and other cognitive lapses.

• Cell death shrinks the brain in areas that involve memory (the hippocampus) and higher-level brain functions (the cortex) and thus can be tracked with a form of magnetic resonance imaging that measures brain volume.

• Such shrinkage accelerates and ultimately involves many areas of the brain

Brain shrinkage in AD

DIABETES AND ALZHEIMER DISEASE

Diabetes and Alzheimer’s disease

• Risk of developing dementia is twice as great in diabetes

• DM is associated with greater cognitive decline

• DM may hasten onset of clinical manifestations of AD

• Risk of dementia is also increased in borderline diabetics with hypertension

Type 2 DM And Hypertension As Risk Factors For Poor Cognitive Performance

The Framingham Study• 187 diabetics

• 1624 non-diabetics

• Followed for 30 years

• Diabetics were at greater risk for poor performance in visual memory tasks

• Risk greater with hypertension and with duration of diabetes and insulin use

Diabetes Care, 1997, 20: 1388-95

Functional MRI

• People with AD show altered brain activity in the Default Mode Network

• Set of brain regions active at rest that deactivate during tasks• Abnormal glucose metabolism• Site of fist accumulation of amyloid• T2DM patients show reduced functional connectivity on DMN

POSSIBLE LINKS BETWEEN AD AND T2DM

DM & AD: Why Expect An Association?

• Both conditions are common

- High prevalence with age

- Comparable lifetime risks

• DM is a vascular risk factor

• DM is a metabolic risk factor

Dementia after stroke:the Framingham study

• Diabetes increases risk of stroke and risk of dementia after stroke

Stroke 2004, 35, 1264-1269

DM & AD: Why Expect An Association?

• Both conditions are common

- High prevalence with age

- Comparable lifetime risks

• DM is a vascular risk factor

• DM is a metabolic risk factor

Association of metabolic syndrome with AD :a population based study

The metabolic syndrome (NCEP-ATP III criteria)(adjusting for age, education, APOE, TC) was significantly associated with AD (OR 2.5)

The study found that certain factors increased the risk of developing dementia 27 years later

- Hypertension 24%

- Smoking 26%

- High cholesterol 42%

- DM 46%

Neurology 2006, 67, 843-847

The metabolic syndrome, inflammation and risk of cognitive

decline

• Metabolic syndrome + high inflammation (CRP and IL6 above median): RR= 1.66

• Metabolic syndrome + low inflammation: RR= 1.08

Yaffe et al JAMA 2004, 292: 2237

Dose response: RX Effects

• Better cognitive performance, decreased decline noted in diabetics who:

- Had improved blood sugar control

- Were on treatment

- Were on oral medication

– Mixed results with insulin

Dose response: duration Effects

Lower cognitive function

Greater cognitive decline

With increasing duration of diabetes

EVIDENCE OF INSULIN-SIGNALINGABNORMALITIES IN AD BRAIN

Type 3 Diabetes

• Insulin resistance in the brain in AD is becoming evident even in the absence of systemic diabetes

• for this reason some have referred to AD as “type 3 diabetes”

• There is a growing evidence that insulin resistance and downstream abnormalities in the insulin signaling pathway are present in the AD brain and contribute to the development of cognitive dysfunction in this disease

Steen E et al J Alzheimers Dis 2005;7:63–80de la Monte SM, et al J Diabetes Sci Technol 2008;2:1101–1113

T2DM and Alzheimer’s disease:the role of insulin resistance

• Diabetes and insulin resistance have been shown to be risk factors for Alzheimer’s disease and other forms of dementia

• Insulin dysregulation thought to play a pivotal role in both conditions

• Human hippocampus slices from AD patients stimulated with insulin ex vivo showed reduced insulin signaling first direct evidence of insulin resistance in the human brain

PEILA ET AL 2002 Ronnemaa et al 2008Talbot et al 2012 JCI

Insulin signaling

Mark Yarchoan1and Steven E. Arnold Diabetes 2014;63:2253–2261

Diet and exerciseeffect of 4 week diet on AD

biomarkers

•Delayed visual memory improved after 4 weeks for both groups on low fat diet• CSF Ab increased in healthy adults on high fat diet

Carter et al 2011

Exercise

• 6 months of aerobic exercise vs stretching control improved cognitive dysfunction for older adults as well as for amnestic MCI or prediabetes and reduced plasma levels of ab

• diet + exercise interact such that exercise mitigates effects of unhealthy diet

• Small pilot study – Cognition ↑

– Functional connectivity ↑

– Glutamate ↑

Baker et al 2010, 2012

PTP1B protein tyrosin phosphatases that inhibit insulin signaling

Insulin-sensitizer metformin for mild cognitive impairment and early AD

• First line drug for T2D

• Activated AMPKmTOR/p56k negative feedback to IRS-pSfacilitates activation of IRS1 signaling

• Epidemiologic data show that rates of dementia decreased in T2D patients taking metformin compared to SU and other drugs potential for AD modification and symptomatic relief

Insulin to Treat Alzheimer's DiseaseJust Follow Your Nose?

• Alzheimer's disease (AD) is linked to CNS insulin resistance, and lower cerebrospinal insulin levels.

• The intranasal method of insulin administration was used• This method effectively bypasses the blood–brain barrier to

deliver and target insulin directly from the nose to the brain • A series of acute clinical have shown that increased CNS

insulin action enhances learning and memory processes. • 4 months of intranasal insulin administration (20 IU

insulin/day) preserved not only general cognition but also reduced the loss of metabolic integrity of the brain in adults with mild-to-moderate AD.

Helgi B Schiöth; et al. Expert Rev Clin Pharmacol. 2012;5(1):17-20.

Summary and conclusions

• AD is epidemic secondary to the aging demographic and is now the most costly health care condition

• Diabetes and other metabolic syndrome features are important risk factors for AD,

• Neuropathological studies find severe brain insulin resistance and extensive activation abnormalities in major insulin signaling pathways in AD, irrespective of peripheral diabetes status

• A number of drugs for diabetes restore function in the IRS-Akt pathway that is dysfunctional in AD brain and may prove effective in ameliorating symptoms or modifying AD pathology

Thank you