Ueda2016 diabetes and alzheimer disease - mohamed kamar

1. Diabetes And Alzheimer Disease
What Is The Link?
Mohamed Kamar
Professor Of Diabetes And
Endocrinology
Zagazig Faculty Of Medicine

2. 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

4. WHAT IS ALZHEIMER’S DISEASE?

6. 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

7. Amyloid deposition in synapses

8. TAU Buildup
1–5 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

9. TAU Buildup inside cells

10. 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

11. Brain shrinkage in AD

14. DIABETES AND ALZHEIMER DISEASE

15. 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

16. 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

19. 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

20. POSSIBLE LINKS BETWEEN AD AND
T2DM

21. 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

22. Dementia after stroke:
the Framingham study
• Diabetes increases risk of stroke and risk of
dementia after stroke
Stroke 2004, 35, 1264-1269

23. 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

24. 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

26. 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

27. 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

28. Dose response: duration Effects
Lower cognitive function
Greater cognitive decline
With increasing duration of diabetes

29. EVIDENCE OF INSULIN-SIGNALING
ABNORMALITIES IN AD BRAIN

30. 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;7:63–80
de la Monte SM, et al J Diabetes Sci Technol 2008;2:1101–1113

31. 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 2008
Talbot et al 2012 JCI

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

33. Diet and exercise
effect 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

34. 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

35. PTP1B protein tyrosin phosphatases
that inhibit insulin signaling

36. Insulin-sensitizer metformin for mild
cognitive impairment and early AD
• First line drug for T2D
• Activated AMPKmTOR/p56k negative
feedback to IRS-pS facilitates 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

37. Insulin to Treat Alzheimer's Disease
Just 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.

38. 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

39. Thank you