Summary

Jack de la Torre, David Bennett, and Julie Schneider led this live discussion on 21 April 2004. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript:

This live discussion with Jack de la Torre (Case Western Reserve University), David Bennett (Rush University Medical Center), and Julie Schneider (Rush University Medical Center) was held on 21 April 2004.

Participants: Rob Riekse, University of Washington; Geo Serban, Mount Sinai School of Medicine, NY Julie Schneider, Rush University Medical Center; David Bennett, Rush Alzheimer's Disease Center, Rush University, Chicago; Roxana Carare-Nnadiv, School of Medicine, University of Southampton, U.K.; Mark Walker, Southampton University NHS Trust, U.K.; Mark Smith, Robert Rubey, Medical University of South Carolina, Charleston; Amy Borenstein, University of South Florida; Keith Crutcher, University of Cincinnati; Craig Atwood, University of Wisconsin-Madison; Gail Li, University of Washington, Seattle; June Kinoshita, Alzheimer Research Forum; Larry Nault as listed in ARF Profiles; Wang Danling, Tongji Medical College, Wuhan, China; Gjumrakch , CWRU, Pathology; Jack de la Torre, Jim Kallio, caregiver; Alexei Koudinov, Neurobiology of Lipids.

Note: The transcript has been edited for clarity and accuracy.

June Kinoshita
Welcome, everyone. I'm moderating today's chat. I'd like to ask David and Julie to recap the question they were addressing in their study.

David Bennett
We examined the extent to which cerebral infarcts and AD pathology were additive to risk of dementia, or interactive-meaning the two increased risk more than the sum-or both (see Schneider et al 2004 ).

Julie Schneider
In other words, are they additive or multiplicative?

June Kinoshita
And you found that they were additive, correct?

David Bennett
We found an additive effect, meaning infarcts and AD pathology each made a unique, and relatively independent, contribution to dementia.

Craig Atwood
Which pathology are we talking about, amyloid and infarct number and size?

Julie Schneider
We looked at number, volume, as well as location, and the findings were the same.

David Bennett
AD pathology was standard silver stained counts of neuritic plaques (NP), diffuse plaques (DP), and neurofibrillary tangles (NFT).

Gjumrakch Aliev
I do not think that these two pathologies can be separated. This is one process.

Craig Atwood
I agree with Gjumrakch .

Gjumrakch Aliev
We need to look back before any amyloid or any stroke conditions have appeared!

David Bennett
I'm not sure I get Gjumrakch 's point.

June Kinoshita
I think Gjumrakch is suggesting that upstream factors may result in vascular disease and AD…?

Jack de la Torre
I just want to say for the record, this debate or discussion (depending on one's sensitivity) should want to make people think about "what if…?" which to me, are the most important two words in science. In that vein, controversy is not only good, but also desirable.

Craig Atwood
"Why" is also a good word.

Julie Schneider
I should clarify. We only looked at ischemic old macroscopic infarctions. And yes, we also looked at lacunar infarctions.

David Bennett
There was no relation between AD pathology and infarcts.

Mark Smith
So, Jack, given your hypothesis, how do you explain David's findings?

June Kinoshita
Jack, how does this finding affect your thoughts about how vascular factors and AD may be related? Certainly you provide a compelling set of correlations of overlapping pathology and risk factors (see de la Torre 2004).

Jack de la Torre
In David's study, we need to differentiate between hypoperfusion and ischemia. They looked at stroke, which is only one of the many risk factors of AD etiology.

Gjumrakch Aliev
Physicians or pathologists are able to see pathology at the later stage when clinical symptoms appear to be permanent features of these patients.

Julie Schneider
If your theory is correct, wouldn't you expect there to be a relationship between ischemic infarctions and AD pathology.

Gjumrakch Aliev
Hypoperfusion comes first and then ischemia or other changes occur. AD pathology and ischemia are products of hypoperfusion.

Craig Atwood
Gjumrakch , what causes the hypoperfusion, then, if it is an underlying cause of the AD and infarct pathology?

Jack de la Torre
There is a relationship between ischemia and AD, but the primary trigger begins as brain hypoperfusion and an added vascular burden such as a vascular risk factor.

David Bennett
We looked at only one aspect of the spectrum of cardiovascular disease (CVD)—old gross infarcts. These are also the ones which appear to be related to clinical disease.

Amy Borenstein
How do white matter hyperintensities figure in here? (Subclinical infarcts?).

Roxana Carare-Nnadi
Did you assess the degree of amyloid angiopathy?

June Kinoshita
Let's let David and Julie answer Amy's question, and also Roxana's.

David Bennett
Good question. We didn't measure white matter changes that were not infarcts.

Julie Schneider
We did not look at white matter hyperintensities specifically. Subclinical infarctions were not as strongly related to clinical disease, as shown in an earlier manuscript. No, we did not assess amyloid angiopathy specifically.

Mark Walker
If macroscopic infarct was the only aspect of CVD entered into the analysis, then perhaps results would have been considerably different if other variables (imaging, histology) were added into the analysis.

Amy Borenstein
The Nun Study found that subclinical infarctions interacted with AD pathology to cause the dementing syndrome.

Julie Schneider
We did look at microscopic infarctions and there was also no interaction with AD pathology.

David Bennett
We were unable to replicate the findings from the Nun Study.

June Kinoshita
Are there any other questions about the pathology findings from David and Julie's paper? Let's wrap up this topic before we move on to the next.

Craig Atwood
Did you look in the posterior cingulate area?

Julie Schneider
All areas were evaluated for macroscopic infarctions, including posterior cingulate.

Craig Atwood
What were the results for the posterior cingulate? Was there a comparable pathology with, say, the areas of the entorhinal cortex?

David Bennett
We did not assess posterior cingulate in the prior study. But that's an important area, and we are doing it now in a follow-up study.

Jack de la Torre
Risk factors for brain vascular disease, such as diabetes, atherosclerosis, hypercholesterolemia, coronary artery disease, hypertension, stroke, hyperhomocysteinemia, and aging are also risk factors for AD. Therefore, factors that predispose to cerebrovascular and cardiac diseases also increase the risk for AD.

David Bennett
Jack, we agree. The question is mechanism. It could be that they cause infarctions, which add to risk of dementia.

Mark Smith
Is congestive heart disease, which likely causes hypoperfusion, a risk for AD?

Jack de la Torre
 Yes.

June Kinoshita
David, great segue into the mechanism topic. So, perhaps we can dig deeper into hypoperfusion.

Jack de la Torre
Remember, aging already involves brain hypoperfusion.

Amy Borenstein
In my view, vascular risk factors can show up as risk factors for AD because they "bring out" the dementia when AD pathology is also present. I think this is what David and Julie's paper says and I agree with it.

David Bennett
I agree with Amy because she agrees with us!

Jack de la Torre
Certainly not. Let me explain. Many vascular risk factors already exist much before any AD symptoms or even mild cognitive impairment (MCI); atherosclerosis, head trauma, smoking, hypertension, cardiac disease, and diabetes are just a few of these risk factors that can be present decades before AD. For example, epidemiological data including the Rotterdam Study, the Kungsholmen project, EURODEM, the Honolulu-Asia study, and others strongly support a vascular role in precipitating AD. Also, the Whitehall Study (see Singh-Manoux et al, 2003), showed in 1600 subjects that vascular disease predicts poor cognitive function in addition, brain blood flow studies can predict AD at the MCI stage and PET studies even prior to MCI. Drugs THAT mildly help AD symptoms all improve CBF mildly. This is only a brief explanation, because I and others have written extensively on this subject.

Julie Schneider
But if these increase risk for infarctions and infarctions decrease the threshold for dementia, this may be the mechanism for increased risk.

David Bennett
Yes, and….

Craig Atwood
Perhaps we should do as Mark suggests and study heart disease!

Julie Schneider
I think that the epidemiologic studies support either mechanism.

Jack de la Torre
Coronary artery by-pass grafts (CABG) may be another important risk factor that has not been investigated fully.

Gjumrakch Aliev
Jack, I think we need to add one more issue. Vascular lesions induced by chronic hypoperfusion appear to be the primary target for AD.

June Kinoshita
Jack, do you think that hypoperfusion is the point of convergence, where these multiple and diverse risk factors meet, and from there events are set in motion that lead to AD? Or does one have to go further upstream?

Amy Borenstein
The epidemiological data show that vascular factors lead to an earlier presentation of dementia/AD. We all seem to agree that vascular factors are important in increasing risk for AD, but we are discussing whether there is a direct effect or whether vascular factors are "enabling" factors for bringing out the dementia.

Julie Schneider
Again, CABG is probably related to subclinical infarction, which decreases the threshold for expressing dementia.

Roxana Carare-Nnadi
In the review published in Lancet (see link on ARF website ), the vascular hypothesis (hypoperfusion leading to neuroglial energy crisis) is a clear explanation for the neurodegeneration, but how does hypoperfusion lead to/explain amyloid accumulation?

Jack de la Torre
When you combine aging (chronic brain hypoperfusion) with a vascular risk factor (more hypoperfusion), you get more reduced cerebral blood flow; eventually this turns sour for the subject because the neurons develop a metabolic energy crisis.

Craig Atwood
Roxana, hypoperfusion will lead to death of neurons and amyloid-β production. Amyloid is a marker of degeneration, and unlikely the primary cause. (Don't throw rocks!)

Gjumrakch Aliev
It has been clearly shown that after heart transplantation, patients always get dementia!

Amy Borenstein
Gjumrakch , "always" is a strong word!

David Bennett
If infarcts and AD pathology had a common etiopathogenesis, we would expect them to be related, but they were not.

Mark Smith
Anyone buy into the coincidence that neurons and cardiac cells are postmitotic? Mechanism?

Jack de la Torre
Animal studies show induced ischemia increases amyloid deposition.

Gjumrakch Aliev
Amyloid can be accumulated after any type of damage. Ischemia is only one factor inducing amyloid deposition.

Alexei Koudinov
I agree with Gjumrakch .

Gjumrakch Aliev
Thanks, Alexei. I think we need to focus on the reasons, not the consequences of the brain lesions or damage!

Craig Atwood
Gjumrakch makes a good point; any degeneration will result in amyloid-β generation and deposition (e.g., head injury or toxicity in vitro).

Julie Schneider
Hippocampal sclerosis is a common age-related pathology seen with Alzheimer's disease and vascular dementia. Perhaps this is another mechanism by which vascular risk factors increase the risk of dementia.

David Bennett
I agree that we need to do antibody-specific staining for amyloid (and tau) before discounting the association. We are doing that.

June Kinoshita
Will you be ready to present the results in Philadelphia, David?

David Bennett
June, we are getting close, with only a third of subjects having infarcts. We need amyloid and tau data on at least 150 cases—a time-consuming endeavor.

June Kinoshita
Thanks, David.

Julie Schneider
The hypoperfusion is in the regions that are most susceptible to AD pathology, but not a vascular territory.

June Kinoshita
Hi, Julie. Can you clarify what you mean by "vascular territory"?

Julie Schneider
Vessels that supply the brain have specific territories; AD pathology does not follow these territories or even the watershed areas.

June Kinoshita
Thanks, Julie.

Jack de la Torre
Also, asymptomatic patients at risk for AD exhibit marked alterations in cerebral perfusion, as assessed by PET, SPECT, or MRI. Because hypoperfusion precedes the onset of cognitive decline; it cannot be attributed to the brain dysfunction produced by the disease.

Jack de la Torre
There is intriguing evidence that Aβ production in AD may be a neuroprotective reaction against some stress: oxidative, trauma, ischemia, etc. Any comments?

Mark Smith
Jack, see Free Radic Biol Med, "Tau and Amyloid-β serve antioxidant function." (Smith et al 2002).

Jack de la Torre
I saw it.

Craig Atwood
Jack, unlikely to be oxidative stress (unpublished results). When a cell undergoes apoptosis, it produces amyloid-β, whether it has been induced to die via overwhelming oxidative stress or other agents.

Gjumrakch Aliev
Craig, a large neuron does not have a chance to die via apoptosis, and this is already shown in a different model, including human study.

Jack de la Torre
Craig, you may be right.

Alexei Koudinov
To Dr. de la Torre's point, I would add that Aβ is also related to lipid (particularly cholesterol) metabolism, and in synaptic function. We discuss both items in our two recent articles (Neurobiol Lipids and Acta Neurobiol Exp).

Gjumrakch Aliev
Amyloid is the product of brain lesions.

Julie Schneider
Gjumrakch , what brain lesions?

Gjumrakch Aliev
Julie, how we need to understand AD pathology does not follow….

Craig Atwood
Gjumrakch , then where are they going?

June Kinoshita
Gjumrakch , what's the citation on that?

Gjumrakch Aliev
June, the citation is in J. Neuroscience, I think, 2001. The study was done in a gerbil model of brain ischemia. In addition, we did not find any apoptotic neuron in human AD brain biopsy as well as postmortem tissue. Large neuron can be compared to an airplane. They do not have chance to die slowly.

Craig Atwood
Gjumrakch , did you do any gerbil studies?

Jack de la Torre
Let me also say that no animal data that examines a disease complex, no matter how brilliant the experiment, can ever substitute for relevant human data. This is axiomatic and undisputable.

Roxana Carare-Nnadi
However, animal studies using intracerebrally injected tracers show deposition of these tracers in perivascular spaces in a manner/pattern comparable to cerebral amyloid angiopathy (CAA). Would you consider Aβ accumulation a result of failure of the physiologic mechanism of interstitial fluid (ISF) drainage?

Julie Schneider
Jack, there are other diseases that cause chronic cerebral ischemia, e.g., Moyamoya, but do not predispose to AD. Explanation?

Jack de la Torre
Ischemia has to affect the right place and age. Moyamoya affects usually children who develop ischemic or hemorrhagic stroke often in pia mater vessels. That is why some strokes in non-cognitive brain regions, even in the elderly, do not lead necessarily to AD.

Mark Smith
Craig, neurons die but not by apoptosis (we discussed this in Science/Nature several years ago, see Perry et al 1998 and Perry et al 1998).

Craig Atwood
Okay, apoptosis was the wrong word. Neuronal death, then.

Mark Smith
Then yes, neurons do die!

Craig Atwood
Wonderful news!

David Bennett
Not for the neurons.

Julie Schneider
Jack, so, your suggestion is that it has to be global rather than focal ischemia?

Jack de la Torre
Julie, usually it is global hypoperfusion, ischemia may not be a proper description because it can involve focal, non-vital brain regions!! Silent stroke (which some of us here may have) affects millions in the world, and they are at risk for AD. But, some silent strokes never lead to AD. Any comments?

Julie Schneider
Again, our data suggests an additive effect of all types of infarctions. No interaction with AD pathology.

Amy Borenstein
Jack, AD is a threshold disease, and silent/overt strokes, in addition to other vascular risk factors, increase the slope for earlier presentation of dementia/AD.

David Bennett
Jack, we did not find an association between subclinical infarcts and dementia. However, we might still see it with a much larger sample size.

Jack de la Torre
Remember, ischemia is measurable (OEF, CMRO2, etc.), but hypoperfusion may go unnoticed for a long time. Also, mild or moderate hypoperfusion is usually not associated with severe metabolic changes such as influx of calcium and sodium ions and prolonged decreases in ATP and increases in lactate levels, that and neuronal damage may come much later.

Gjumrakch Aliev
Jack, hypoperfusion can occur any minute in any brain area. Often, the process can be global such as head trauma or total ischemia or hypoxia (or correctly, anoxia).

Jack de la Torre
I agree.

Julie Schneider
If indeed there is hypoperfusion causing AD, wouldn't you expect the watershed regions and selective vulnerable neurons to be the only ones involved in AD pathology, rather than the more global changes we see?

June Kinoshita
Do imaging studies support the idea of widespread or more global hypoperfusion in people at risk of AD? I'm familiar only with studies showing hypoperfusion in focal regions.

Gjumrakch Aliev
June, please do not forget about the technical difficulty of the technique and the likelihood of detecting measurable changes.

Julie Schneider
June, I agree. That is an important point. There is no evidence of global ischemia on these scans.

Gjumrakch Aliev
Julie, what's the percentage of ischemia that can be detected by scan?

Julie Schneider
Gjumrakch , don't know the percentages.

Craig Atwood
Julie, depends on the diameter of the vessels, and I'd suggest that those in hippocampus are smaller than elsewhere in less affected regions of the brain.

Jack de la Torre
Watershed regions are seen in stroke, not usually with hypoperfusion.

Roxana Carare-Nnadi
Watershed regions would not be the only ones involved; changes would be noticed in proximal arterial territories (cortical, leptomeningeal).

Mark Smith
ApoE is a risk factor for vascular changes but is this only in whites? Since there is a difference in races and in AD susceptibility?

Jack de la Torre
ApoE is a risk factor for cardiac and cardiovascular diseases.

Mark Smith
In all races?

Jack de la Torre
Hypometabolism/hypoperfusion is both cortical as well as subcortical.

Craig Atwood
David, so with both subclinical infarcts and AD, you might expect amyloid deposition if it is a response to neurodegeneration?

David Bennett
Craig, I'm not sure I understand the question. Our study may not have had sufficient power to detect an association with subclinical infarcts. Alternatively, we might yet get a different answer with amyloid immunostaining than with silver staining techniques. Is that what you were looking for?

Craig Atwood
David, what is the amyloid load with infarcts versus the AD brain? When we say pathology for amyloid, are we really just saying neurodegeneration (cell death)?

David Bennett
Craig, we are measuring amyloid load, and counting neurons, but I don't have the answer yet.

Mark Smith
Craig, amyloid doesn't really relate to neurodegeneration.

Gjumrakch Aliev
Craig, measurement of amyloid load and/or counting neurons has nothing to do with AD etiopathology!

Craig Atwood
Mark, has anyone looked at neuron loss stereotaxically and measured amyloid load?

Mark Smith
Not exactly, but there is little to no neuronal loss in normal aging by stereotaxic measures, yet there is often amyloid!

Gjumrakch Aliev
Craig, many things need to be done in science. You can also study stereotaxicity of glial cells. Because nobody did this kind of study.

Craig Atwood
I agree cognition doesn't correlate with amyloid load, but I haven't seen the normal aging data. Besides, how do you know localized regions haven't lost neurons, or deposited amyloid as a response to their reentry into the cell cycle?

David Bennett
Craig, amyloid is related to cognition. But you lose the effect after controlling for tau (see Bennet et al 2004 ). We think that means that tau mediates the effect of amyloid on cognition, but not that it is unimportant.

Craig Atwood
David, okay.

Jack de la Torre
The notion that presence of cerebrovascular disease is an exclusion criterion for AD diagnosis has stunted any real progress in AD research. Any comments?

David Bennett
I agree with Jack's statement above. The field would be much better not excluding coexisting diseases from the diagnosis of AD.

Mark Smith
Depends whether you are a lumper or a splitter, I guess!

Julie Schneider
Agree completely. Very often, it is a mixed pathology. We need to be looking at both pathologies.

Amy Borenstein
You can still be diagnosed with possible AD (by National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria) and included these in analyses.

Julie Schneider
By splitting, you are excluding about one-third of real persons with AD.

Amy Borenstein
I agree with Julie.

June Kinoshita
Jack, Julie, and David, should there be a revision in the diagnostic criteria?

Jack de la Torre
 Absolutely!!!

Mark Smith
I agree, but since one-third normal aged have senile plaques (SP)/neurofibrillary tangles (NFT) for diagnosis of AD, then CVD may simply fool the pathologist into diagnosing the dementia to mixed AD/vascular dementia (VaD).

Jack de la Torre
AD should be regarded as a "vasocognopathy" (a new term I've coined, see Neurol Res July, 2004 issue). The evidence for AD as a vascular disorder is so powerful that we need to revise our thinking for the last 25 years.

Amy Borenstein
Jack, do you then think that there is no "pure" AD?

Jack de la Torre
Amy, there is probably no pure AD or VaD.

Julie Schneider
I am not sure I agree at this point that AD is a vascular disease. I think we might be talking about two very common pathologies that often coexist in the aging brain and contribute to dementia.

Amy Borenstein
I disagree; what about young cases who don't have a vascular contribution?

Julie Schneider
Yes, agree. I don't have numbers, but my experience is that the younger cases and hereditary cases are more often pure than the older cases.

Craig Atwood
Sounds like AD is just "aging."

Jack de la Torre
There will be a special issue of Neurological Research in July 2004 discussing the role of vascular factors in AD and VaD. Hopefully, the issue will be available at the Philadelphia meeting.

Amy Borenstein
Maybe we should study "dementia" instead of NINCDS (National Institute of Neurological and Communicative Diseases) criteria?

Julie Schneider
Amy, yes, I think that often there are combined pathologies in the real world causing dementia. Not only infarctions, but also Lewy body disease, etc.

Amy Borenstein
Combined path is common as age increases.

Jim Kallio
How does ischemia from head trauma fit into this picture overall.

Jack de la Torre
Head injury (severe) is known to reduce brain blood flow for long time periods.

June Kinoshita
Jack, how long? Months? Years?

Jack de la Torre
June, years, but Aβ is sometimes seen right after head trauma.

Mark Smith
Jack, but then it disappears!

Alexei Koudinov
Jack, Mark, the disappearance is another good proof of a transitory and/or compensatory nature of amyloid deposits.

Gjumrakch Aliev
I agree with Alexei. Amyloid is compensatory reaction of the brain tissue to the action of injury stimuli. In addition, amyloid can be produced in any brain cells.

Craig Atwood
Disappearance is everything!

Amy Borenstein
In studies about 15-20 years ago, it was shown that head trauma results in Aβ deposition (see Graham et al 1995).

Julie Schneider
Dementia pugilistica shows diffuse plaques and sometimes some tangles, but not typical AD pathology.

Gail Li
Besides aging, ApoE4 allele is another risk factor for AD found in epidemiological studies consistently. What's the role of ApoE genotype in the hypoperfusion theory?

Jack de la Torre
As I said, ApoE4 is the precursor of reduced cerebral blood flow (CBF).

Julie Schneider
I am presenting data at the AAN next week showing that ApoE4 increases odds of cerebral infarction.

Gjumrakch Aliev
Gail, hypoperfusion can be induced by any factor. Genetic or exogenous!

Gail Li
Do we know the pathway between reduced CBF and ApoE4?

Mark Smith
Jack, do patients with Down's syndrome who go on to develop AD pathology show hypoperfusion?

Gjumrakch Aliev
Mark, yes! Down's syndrome shows clear hypoperfusion induced by genetic abnormality.

Jack de la Torre
Mark, it's been shown that Down's patients develop blood flow and capillary problems before senile plaques; see Buee, 1997 ).

June Kinoshita
Mark, that reminds me of an interesting factoid I learned from Judah Folkman. People with Down's syndrome never develop solid tumor, and he thinks this may be due to the overexpression of an antiangiogenic factor on Chr 21.

Mark Smith
June, interesting!

Gjumrakch Aliev
June, regarding solid tumor. Usually Down's patients do not have a long enough life to develop solid tumor.

June Kinoshita
We have 10 minutes left of our allotted time. I'd like to ask people to propose productive future studies to address the role of vascular factors in AD. Can we start with Jack, David, and Julie, and then open the floor to the audience?

Jack de la Torre
The difference between AD and VaD in my opinion is either slow or sudden CBF reduction.

David Bennett
Our plan is to see if vascular factors related to dementia (e.g., diabetes, hypertension) do so through an association with infarcts or with AD pathology.

Roxana Carare-Nnadi
Aging is associated with arteriosclerosis (and hypoperfusion). Vascular changes present especially at capillary level (basement membrane changes) and change the physiological interactions of soluble Aβ with basement membrane components; this might promote the formation and deposition of fibrillar Aβ?

Julie Schneider
June, I think that more work looking at the brain changes associated with AD such as small vessel disease (lipohyalinosis), white matter changes, amyloid angiopathy, and hippocampal sclerosis, and whether these pathologies merely accompany AD pathology or interact with AD pathology and cause a multiplicative effect, may be of interest.

Roxana Carare-Nnadi
Absolutely agree.

Jack de la Torre
To get back to the hypoperfusion story in AD, can we say that it would be absurd to wave off the dozens of epidemiologic studies showing that vascular-related risk factors increase the chance of developing AD? It is like saying that cigarette smoking and lung cancer, or heart disease, are associated by coincidence.

Amy Borenstein
Jack, of course those epidemiological studies should not be dismissed! It is their interpretation….

Gjumrakch Aliev
Jack, we need to use strong words. Vessel hypoperfusion is not risk, but primary factor for the development of any brain pathology the consequence of this damage is a cognitive problem and future amyloid, etc.

Amy Borenstein
Jack, but they can all be interpreted as contributing to lowering threshold.

Craig Atwood
Jack, the same can be said for reproductive hormones given the large number of epidemiological studies.

Amy Borenstein
To follow up on David's point: I think you have to have the whole causal mechanism to study; a good handle on risk factors (measurement and timing); clinical diagnosis; and pathology on almost everyone. Very hard to do. The Rotterdam Study and Nun Study can do this.

Julie Schneider
Agree. The studies that David mentioned that our group is doing may help to sort out the mechanism by which these risk factors work.

Mark Smith
Based on today, I start exercising tomorrow! Give up the cigarettes and start drinking more!

Jack de la Torre
But besides the epidemiological studies supporting a vascular role for AD, there are many other studies, neuroimaging, pharmacotherapy, etc.

Jim Kallio
So how do the results from the WHI study fit into this picture, too? Although the results seem to be yo-yoing around now.

Craig Atwood
Jim, don't get me started…. WHI studies were performed with medroxyprogesterone and conjugated equine estrogens, not 17β-estradiol and progesterone, so interpretation is difficult.

Jim Kallio
 Sorry.

Jack de la Torre
We also need to look at vascular nitric oxide in AD, a sneaky molecule!

June Kinoshita
In our final few minutes, could we discuss the implications for treatment, identifying people at risk of AD, etc.?

Craig Atwood
Does the Spark's Lipitor study excite anyone?

Julie Schneider
June, We (clinicians) need to be paying more attention to vascular risk factors and vascular health for decreasing the risk of AD, since AD is often mixed and can be precipitated by cerebral infarction.

Jack de la Torre
We need above all to give AD patients a chance of hope for the future; present AD research into amyloid is doing little in this regard.

Gjumrakch Aliev
Julie, vessel angiopathy and AD are not mixed! First, changes occur in vessels. Amyloid is a consequence of a vessel problem.

Craig Atwood
Lipitor and halting cognitive decline. Does cholesterol have anything to do with vasculature?

Jim Kallio
I would think cholesterol has vast implications on that.

Riekse
Any other thoughts with cholesterol and AD?

Alexei Koudinov
I think that lipid metabolism and oxidative stress cascade could provide a pathogenetic explanation for the vascular factors in AD. Riekse, please visit Neurobiology of Lipids for more information on cholesterol and AD; also see related ARF live discussion transcript and ARF hypothesis page).

Alexei Koudinov
Gjumrakch , I would like to use this nice opportunity to thank Dr. de la Torre for his Lancet Neurology article (a background major reading, freely available on the ARF web site), and for the article analysis of the failure of the amyloid hypothesis. The failure of the amyloid hypothesis was most recently enlightened in two Wall Street Journal articles (of April 9 and April 16, 2004) that are available for free.

Wangdanling
Tau protein is more relative to dementia than amyloid; why not discuss the possible relationship between tau and vascular factor.

David Bennett
We are looking at tau, too.

Alexei Koudinov
Addressing tau and Aβ interrelation, coined above. I think that both can serve independent compensatory function that we started to discuss three years ago (see Koudinov and Koudinova 2001), Aβ may affect lipid metabolism, or cholesterol uptake, for example, while tau changes (that I hardly can call pathological, as hyperphosphorylation happens at certain ontogenesis stages and then is gone) may help to rearrange neuronal cytoskeleton to help restore neurotransmission, for example. Such looks provide a clue for the explanation of the overlap of neurodegeneration features across different neurodegenerative diseases (in Parkinson's, for example).

June Kinoshita
Our time is up. Thank you everyone for attending today. You're all welcome to keep chatting, of course. The room is open indefinitely.

Julie Schneider
June, Thank you for inviting me to participate.

 

Robert Rubey
I have to run, I enjoyed the discussion. Thanks!

June Kinoshita
Special thanks and hearty applause to Jack, David, and Julie.

Roxana Carare-Nnadi
Very interesting; thank you.

Amy Borenstein
Nice job! Thanks.

Dara Dickstein
Very interesting conversation. Thank you.

Jack de la Torre
Good show!

Mark Smith
Great work!

Gail Li
 Thanks.

Jim Kallio
Thanks, everyone…well done.

Riekse
Thank you for the interesting discussion.

Craig Atwood
June, thanks for another stimulating discussion, and bye.

 

Background

Background Text

Introduction

From the earliest history of Alzheimer’s disease, cerebrovascular mechanisms have been suspected of playing a role in the pathogenesis of the disease. Until recently, the public imagination accepted the notion that “a hardening of the arteries” was to blame for senile dementias. Although scientific research has since directed greater attention to molecular mechanisms centered on amyloid-beta, tau inclusions, etc., a large and diverse body of evidence from studies in humans and in experimental models has pointed consistently to a link between Alzheimer’s and vascular factors. In his recent review in Lancet Neurology, Jack de la Torre argues that “the data supporting AD as a primary vascular disorder are more convincing” than data supporting the neurotoxicity of amyloid deposition. He goes on to say that studies of vascular factors indicate “that chronic brain hypoperfusion is linked to AD risk factors, AD preclinical detection and pharmacotherapeutic action of AD symptoms.”

De la Torre summarizes the evidence as follows:

1. Epidemiologic studies show that practically all of the reported risk factors for AD are related to vascular functions and have an established association with cerebral hypoperfusion. These findings further suggest that the presence of such vascular-related risk factors in the elderly tends to reduce cerebral blood flow to a level that can generate physiometabolic, cognitive and neurodegenerative changes in the brain.

2. AD and vascular dementia (VaD) share most of these vascular risk factors.

3. Pharmacotherapy that marginally improves cerebral hypoperfusion also marginally improves AD symptoms. This includes most of the drugs that have been reported to be useful in AD for the past 25 years.

4. Preclinical detection of AD can be made from regional cerebral blood flow and glucose uptake measurements.

5. Major clinical symptoms in AD and VaD overlap to a significant extent.

6. Cerebrovascular and neurodegenerative pathologic markers also overlap; these include senile plaques and neurofibrillary tangles observed at autopsy.

7. Cerebral infarction increases the incidence of AD by 50 percent.

8. Chronic cerebral hypoperfusion and oxidative stress can trigger hypometabolic, cognitive, and neurodegenerative changes in animals and humans;

9. About one-third of all autopsied AD brains show evidence of stroke, and nearly all AD brains reveal some form of cerebrovascular pathology.

10. Individuals diagnosed with mild cognitive impairment convert to AD or VaD in 48 percent and 56 percent of cases ,respectively, within several years.

Despite such compelling arguments, the evidence remains circumstantial. Correlation famously does not equal causation, and demonstrating the latter has not been easy. A newly published study by Julie Schneider , David Bennett and colleagues, for example, exhaustively examined clinical and neuropathological data from 153 deceased subjects from the famous Religious Orders Study cohort and found that “cerebral infarctions independently contribute to the likelihood of dementia but do not interact with AD pathology to increase the likelihood of dementia beyond their additive effect.”

While this finding suggests that infarctions by themselves only contribute to, rather than cause, Alzheimer pathology, it leaves unanswered whether hypoperfusion and other vascular factors play a role in the etiology of AD. We invite discussion participants (online and offline) to contribute their ideas regarding the role of vascular factors. (See, for example, the hypothesis of Aβ drainage that Roy Weller and James Nicoll propose as an explanation of how cerebrovascular disease contributes to AD. Their thinking integrates vascular factors with the amyloid hypothesis.) What are possible mechanisms to explain the association between vascular disease and AD, what are the implications for diagnosis and treatment, and which future directions for research could lead to new insights? –June Kinoshita, Executive Editor

 

Some Topics for Discussion

1) Why do AD and VaD overlap in their clinical symptoms, pathology, disease outcome, and treatment potential?

2) Should AD that contains vascular damage always be considered a vascular dementia, or is it time to modify our definitions?

3) Does a vascular etiology explain the anatomical and cellular specificity of Alzheimer pathology?

4) If cerebral infarcts contribute independently to the risk of dementia, as asserted by Schneider, et al., does this fact alone argue against Alzheimer’s being a primary vascular disorder, or does the Schneider, et al., study leave open the possibility that cerebral hypoperfusion is still the underlying cause of AD?

5) Why do cerebrovascular and heart disease (and about two dozen other reported risk factors) increase the risk of AD or VaD?

6) Does oxidative stress trigger Abeta production in brain or the other way around? Evidence for either situation?

7) Is a vascular etiology incompatible with Alzheimer’s being neurodegenerative? Can these two perspectives be united?

8) What new lines of investigation might bring about dramatic progress in AD?

Primary References

De La Torre JC. Is Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, dogma and dialectics. Lancet Neurology 2004; 3:184-90. Full text (.pdf)

Schneider JA, Wilson RS, Bienias JL, Evans DA, Bennett DA. Cerebral infarctions and the likelihood of dementia from Alzheimer pathology. Neurology 2004 April; 62. Abstract

References Supplied by Jack de la Torre:

Aliev G, Seyidova D, Neal ML, Shi J, Lamb BT, Siedlak SL, Vinters HV, Head E, Perry G, Lamanna JC, Friedland RP, Cotman CW. Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a central target for the development of human AD and AD-like pathology in aged transgenic mice. Ann N Y Acad Sci. 2002 Nov;977:45-64. Abstract

Aliev G, Seyidova D, Lamb BT, Obrenovich ME, Siedlak SL, Vinters HV, Friedland RP, LaManna JC, Smith MA, Perry G. Mitochondria and vascular lesions as a central target for the development of Alzheimer's disease and Alzheimer disease-like pathology in transgenic mice. Neurol Res. 2003 Sep;25(6):665-74. Abstract

Aliev G, Smith MA, Seyidov D, Neal ML, Lamb BT, Nunomura A, Gasimov EK, Vinters HV, Perry G, LaManna JC, Friedland RP. The role of oxidative stress in the pathophysiology of cerebrovascular lesions in Alzheimer's disease. Brain Pathol. 2002 Jan;12(1):21-35. Review. Abstract

Arendash GW, Su GC, Crawford FC, Bjugstad KB, Mullan M. Intravascular beta-amyloid infusion increases blood pressure: implications for a vasoactive role of beta-amyloid in the pathogenesis of Alzheimer's disease. Neurosci Lett. 1999 Jun 11;268(1):17-20. Abstract

Breteler MM. Vascular involvement in cognitive decline and dementia. Epidemiologic evidence from the Rotterdam Study and the Rotterdam Scan Study. Ann N Y Acad Sci. 2000 Apr;903:457-65. No abstract available. Abstract

Buee L, Hof PR, Delacourte A. Brain microvascular changes in Alzheimer's disease and other dementias. Ann N Y Acad Sci. 1997 Sep 26;826:7-24. Review. Abstract

Cacabelos R, Fernandez-Novoa L, Lombardi V, Corzo L, Pichel V, Kubota Y. Cerebrovascular risk factors in Alzheimer's disease: brain hemodynamics and pharmacogenomic implications. Neurol Res. 2003 Sep;25(6):567-80. Review. Abstract

Chen GJ, Xu J, Lahousse SA, Caggiano NL, de la Monte SM. Transient hypoxia causes Alzheimer-type molecular and biochemical abnormalities in cortical neurons: potential strategies for neuroprotection. J Alzheimers Dis. 2003 Jun;5(3):209-28. Abstract

De Jong GI, Farkas E, Stienstra CM, Plass JR, Keijser JN, de la Torre JC, Luiten PG. Cerebral hypoperfusion yields capillary damage in the hippocampal CA1 area that correlates with spatial memory impairment. Neuroscience. 1999;91(1):203-10. Abstract

de la Torre JC. Alzheimer's disease: how does it start? J Alzheimers Dis. 2002 Dec;4(6):497-512. Review. Abstract

de la Torre JC. Alzheimer disease as a vascular disorder: nosological evidence. Stroke. 2002 Apr;33(4):1152-62. Review. Abstract

de la Torre JC, Stefano GB. Evidence that Alzheimer's disease is a microvascular disorder: the role of constitutive nitric oxide. Brain Res Brain Res Rev. 2000 Dec;34(3):119-36. Review. Abstract

de la Torre JC. Critically attained threshold of cerebral hypoperfusion: can it cause Alzheimer's disease? Ann N Y Acad Sci. 2000 Apr;903:424-36. Review. Abstract

de la Torre JC. Hemodynamic consequences of deformed microvessels in the brain in Alzheimer's disease. Ann N Y Acad Sci. 1997 Sep 26;826:75-91. Review. Abstract

de la Torre JC, Mussivand T. Can disturbed brain microcirculation cause Alzheimer's disease? Neurol Res. 1993 Jun;15(3):146-53. Review. Abstract

De Santi S, de Leon MJ, Rusinek H, Convit A, Tarshish CY, Roche A, Tsui WH, Kandil E, Boppana M, Daisley K, Wang GJ, Schlyer D, Fowler J. Hippocampal formation glucose metabolism and volume losses in MCI and AD. Neurobiol Aging. 2001 Jul-Aug;22(4):529-39. Abstract

Farkas E, Luiten PG. Cerebral microvascular pathology in aging and Alzheimer's disease. Prog Neurobiol. 2001 Aug;64(6):575-611. Review. Abstract

Farkas E, De Jong GI, de Vos RA, Jansen Steur EN, Luiten PG. Pathological features of cerebral cortical capillaries are doubled in Alzheimer's disease and Parkinson's disease. Acta Neuropathol (Berl). 2000 Oct;100(4):395-402. Abstract

Goldsmith HS, Wu W, Zhong J, Edgar M. Omental transposition to the brain as a surgical method for treating Alzheimer's disease. Neurol Res. 2003 Sep;25(6):625-34. Abstract

Grammas P, Yamada M, Zlokovic B. The cerebromicrovasculature: a key player in the pathogenesis of Alzheimer's disease. J Alzheimers Dis. 2002 Jun;4(3):217-23. Review. Abstract

Kalaria RN. Comparison between Alzheimer's disease and vascular dementia: implications for treatment. Neurol Res. 2003 Sep;25(6):661-4. Review. Abstract

Hofman A, Ott A, Breteler MM, Bots ML, Slooter AJ, van Harskamp F, van Duijn CN, Van Broeckhoven C, Grobbee DE. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study. Lancet. 1997 Jan 18;349(9046):151-4. Abstract

Huang C, Wahlund LO, Svensson L, Winblad B, Julin P. Cingulate cortex hypoperfusion predicts Alzheimer's disease in mild cognitive impairment. BMC Neurol. 2002 Sep 12;2(1):9. Abstract

Johnson KA, Albert MS. Perfusion abnormalities in prodromal AD. Neurobiol Aging. 2000 Mar-Apr;21(2):289-92. Review. Abstract

Nagata K, Sato M, Satoh Y, Watahiki Y, Kondoh Y, Sugawara M, Box G, Wright D, Leung S, Yuya H, Shimosegawa E. Hemodynamic aspects of Alzheimer's disease. Ann N Y Acad Sci. 2002 Nov;977:391-402. Abstract

Niwa K, Kazama K, Younkin SG, Carlson GA, Iadecola C. Alterations in cerebral blood flow and glucose utilization in mice overexpressing the amyloid precursor protein. Neurobiol Dis. 2002 Feb;9(1):61-8. Abstract

Paris D, Humphrey J, Quadros A, Patel N, Crescentini R, Crawford F, Mullan M. Vasoactive effects of A beta in isolated human cerebrovessels and in a transgenic mouse model of Alzheimer's disease: role of inflammation. Neurol Res. 2003 Sep;25(6):642-51. Abstract

Polidori MC, Marvardi M, Cherubini A, Senin U, Mecocci P. Heart disease and vascular risk factors in the cognitively impaired elderly: implications for Alzheimer's dementia. Aging (Milano). 2001 Jun;13(3):231-9. Review. Abstract

Qiu C, von Strauss E, Fastbom J, Winblad B, Fratiglioni L. Low blood pressure and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Arch Neurol. 2003 Feb;60(2):223-8. Abstract

Rodriguez G, Vitali P, Calvini P, Bordoni C, Girtler N, Taddei G, Mariani G, Nobili F. Hippocampal perfusion in mild Alzheimer's disease. Psychiatry Res. 2000 Dec 4;100(2):65-74. Abstract

Roher AE, Esh C, Kokjohn TA, Kalback W, Luehrs DC, Seward JD, Sue LI, Beach TG. Circle of willis atherosclerosis is a risk factor for sporadic Alzheimer's disease. Arterioscler Thromb Vasc Biol. 2003 Nov 1;23(11):2055-62. Epub 2003 Sep 25. Abstract

Selley ML. Increased concentrations of homocysteine and asymmetric dimethylarginine and decreased concentrations of nitric oxide in the plasma of patients with Alzheimer's disease. Neurobiol Aging. 2003 Nov;24(7):903-7. Abstract

Skoog I, Gustafson D. Hypertension and related factors in the etiology of Alzheimer's disease. Ann N Y Acad Sci. 2002 Nov;977:29-36. Abstract

Verghese J, Lipton RB, Hall CB, Kuslansky G, Katz MJ. Low blood pressure and the risk of dementia in very old individuals. Neurology. 2003 Dec 23;61(12):1667-72. Abstract

Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med. 2003 Mar 27;348(13):1215-22. Abstract

White L, Petrovitch H, Hardman J, Nelson J, Davis DG, Ross GW, Masaki K, Launer L, Markesbery WR. Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants. Ann N Y Acad Sci. 2002 Nov;977:9-23. Abstract

 

Zlokovic BV. Vascular disorder in Alzheimer's disease: role in pathogenesis of dementia and therapeutic targets. Adv Drug Deliv Rev. 2002 Dec 7;54(12):1553-9. AbstractReview.

Additional References

Etiene D, Kraft J, Ganju N, Gomez-Isla T, Gemelli B, Hyman BT, Hedley-Whyte ET, Wands JR, De La Monte SM. Cerebrovascular Pathology Contributes to the Heterogeneity of Alzheimer's Disease. J Alzheimers Dis. 1998 Dec;1(2):119-134. Abstract

Lopez OL, Jagust WJ, Dulberg C, Becker JT, DeKosky ST, Fitzpatrick A, Breitner J, Lyketsos C, Jones B, Kawas C, Carlson M, Kuller LH. Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2. Arch Neurol. 2003 Oct;60(10):1394-9. Abstract

Mattson MP, Haberman F. Folate and homocysteine metabolism: therapeutic targets in cardiovascular and neurodegenerative disorders. Curr Med Chem. 2003 Oct ;10(19):1923-9. Abstract

Sparks DL, Martin TA, Gross DR, Hunsaker JC 3rd. Link between heart disease, cholesterol, and Alzheimer's disease: a review. Microsc Res Tech. 2000 Aug 15;50(4):287-90. Abstract

Comments

 

Evidence continues to accumulate that cerebral hypoperfusion may well prove to be the underlying cause of Alzheimer disease(AD). As one ages, cerebral blood flow(CBF) decreases as a direct reflection of the normal aging process. Coupled with this normally expected drop in CBF are a host of other factors such as hypertension, stress, smoking, diabetes, cholesterol elevations, etc. which further decrease blood flow to the brain. The maintenance of a critical level of CBF is essential if adequate amounts of oxygen and glucose are to be presented to neurons in order to sustain their cellular energy production(ATP). If such a critical CBF is not maintained, insufficient ATP will be produced with the deterioration and the eventual death of the neuron. When a critical mass of neurons die in areas of the brain involved with cognition and memory, AD results.

 

What is becoming more reasonable to believe is that a failing AD brain needs an increasing CBF. Omentum transposition is surgical procedure by which such an increase in additional blood flow can be delivered to the brain over a continuing period of time. The operation has already been shown to have the ability in some AD patients to reverse the symptoms of their disease.

 

If cerebral hypoperfusion turns out to be the underlying cause of AD, the omentum's ability to supply large volumes of blood to critical areas of the brain may explain why omentum transposition has resulted in improvement in AD patients.

 

Omentum transposition is a procedure that can be performed today, and until pharmaceutical and genetic management is developed in the future to prevent and treat AD, omentum transposition should be considered in the treatment of this devastating disease.—Harry S. Goldsmith M.D.

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References

Webinar Citations

  1. Vascular Factors in Alzheimer's Disease

Paper Citations

  1. . Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology. Neurology. 2004 Apr 13;62(7):1148-55. PubMed.
  2. . Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a central target for the development of human AD and AD-like pathology in aged transgenic mice. Ann N Y Acad Sci. 2002 Nov;977:45-64. PubMed.
  3. . Mitochondria and vascular lesions as a central target for the development of Alzheimer's disease and Alzheimer disease-like pathology in transgenic mice. Neurol Res. 2003 Sep;25(6):665-74. PubMed.
  4. . The role of oxidative stress in the pathophysiology of cerebrovascular lesions in Alzheimer's disease. Brain Pathol. 2002 Jan;12(1):21-35. PubMed.
  5. . Intravascular beta-amyloid infusion increases blood pressure: implications for a vasoactive role of beta-amyloid in the pathogenesis of Alzheimer's disease. Neurosci Lett. 1999 Jun 11;268(1):17-20. PubMed.
  6. . Vascular involvement in cognitive decline and dementia. Epidemiologic evidence from the Rotterdam Study and the Rotterdam Scan Study. Ann N Y Acad Sci. 2000 Apr;903:457-65. PubMed.
  7. . Brain microvascular changes in Alzheimer's disease and other dementias. Ann N Y Acad Sci. 1997 Sep 26;826:7-24. PubMed.
  8. . Cerebrovascular risk factors in Alzheimer's disease: brain hemodynamics and pharmacogenomic implications. Neurol Res. 2003 Sep;25(6):567-80. PubMed.
  9. . Transient hypoxia causes Alzheimer-type molecular and biochemical abnormalities in cortical neurons: potential strategies for neuroprotection. J Alzheimers Dis. 2003 Jun;5(3):209-28. PubMed.
  10. . Cerebral hypoperfusion yields capillary damage in the hippocampal CA1 area that correlates with spatial memory impairment. Neuroscience. 1999;91(1):203-10. PubMed.
  11. . Alzheimer's disease: how does it start?. J Alzheimers Dis. 2002 Dec;4(6):497-512. PubMed.
  12. . Alzheimer disease as a vascular disorder: nosological evidence. Stroke. 2002 Apr;33(4):1152-62. PubMed.
  13. . Evidence that Alzheimer's disease is a microvascular disorder: the role of constitutive nitric oxide. Brain Res Brain Res Rev. 2000 Dec;34(3):119-36. PubMed.
  14. . Critically attained threshold of cerebral hypoperfusion: can it cause Alzheimer's disease?. Ann N Y Acad Sci. 2000 Apr;903:424-36. PubMed.
  15. . Hemodynamic consequences of deformed microvessels in the brain in Alzheimer's disease. Ann N Y Acad Sci. 1997 Sep 26;826:75-91. PubMed.
  16. . Can disturbed brain microcirculation cause Alzheimer's disease?. Neurol Res. 1993 Jun;15(3):146-53. PubMed.
  17. . Hippocampal formation glucose metabolism and volume losses in MCI and AD. Neurobiol Aging. 2001 Jul-Aug;22(4):529-39. PubMed.
  18. . Cerebral microvascular pathology in aging and Alzheimer's disease. Prog Neurobiol. 2001 Aug;64(6):575-611. PubMed.
  19. . Pathological features of cerebral cortical capillaries are doubled in Alzheimer's disease and Parkinson's disease. Acta Neuropathol. 2000 Oct;100(4):395-402. PubMed.
  20. . Omental transposition to the brain as a surgical method for treating Alzheimer's disease. Neurol Res. 2003 Sep;25(6):625-34. PubMed.
  21. . The cerebromicrovasculature: a key player in the pathogenesis of Alzheimer's disease. J Alzheimers Dis. 2002 Jun;4(3):217-23. PubMed.
  22. . Comparison between Alzheimer's disease and vascular dementia: implications for treatment. Neurol Res. 2003 Sep;25(6):661-4. PubMed.
  23. . Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study. Lancet. 1997 Jan 18;349(9046):151-4. PubMed.
  24. . Cingulate cortex hypoperfusion predicts Alzheimer's disease in mild cognitive impairment. BMC Neurol. 2002 Sep 12;2:9. PubMed.
  25. . Perfusion abnormalities in prodromal AD. Neurobiol Aging. 2000 Mar-Apr;21(2):289-92. PubMed.
  26. . Hemodynamic aspects of Alzheimer's disease. Ann N Y Acad Sci. 2002 Nov;977:391-402. PubMed.
  27. . Alterations in cerebral blood flow and glucose utilization in mice overexpressing the amyloid precursor protein. Neurobiol Dis. 2002 Feb;9(1):61-8. PubMed.
  28. . Vasoactive effects of A beta in isolated human cerebrovessels and in a transgenic mouse model of Alzheimer's disease: role of inflammation. Neurol Res. 2003 Sep;25(6):642-51. PubMed.
  29. . Heart disease and vascular risk factors in the cognitively impaired elderly: implications for Alzheimer's dementia. Aging (Milano). 2001 Jun 1;13(3):231-9. PubMed.
  30. . Low blood pressure and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Arch Neurol. 2003 Feb;60(2):223-8. PubMed.
  31. . Hippocampal perfusion in mild Alzheimer's disease. Psychiatry Res. 2000 Dec 4;100(2):65-74. PubMed.
  32. . Circle of willis atherosclerosis is a risk factor for sporadic Alzheimer's disease. Arterioscler Thromb Vasc Biol. 2003 Nov 1;23(11):2055-62. PubMed.
  33. . Increased concentrations of homocysteine and asymmetric dimethylarginine and decreased concentrations of nitric oxide in the plasma of patients with Alzheimer's disease. Neurobiol Aging. 2003 Nov;24(7):903-7. PubMed.
  34. . Hypertension and related factors in the etiology of Alzheimer's disease. Ann N Y Acad Sci. 2002 Nov;977:29-36. PubMed.
  35. . Low blood pressure and the risk of dementia in very old individuals. Neurology. 2003 Dec 23;61(12):1667-72. PubMed.
  36. . Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med. 2003 Mar 27;348(13):1215-22. PubMed.
  37. . Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants. Ann N Y Acad Sci. 2002 Nov 1;977:9-23. PubMed.
  38. . Vascular disorder in Alzheimer's disease: role in pathogenesis of dementia and therapeutic targets. Adv Drug Deliv Rev. 2002 Dec 7;54(12):1553-9. PubMed.
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  40. . Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2. Arch Neurol. 2003 Oct;60(10):1394-9. PubMed.
  41. . Folate and homocysteine metabolism: therapeutic targets in cardiovascular and neurodegenerative disorders. Curr Med Chem. 2003 Oct;10(19):1923-9. PubMed.
  42. . Link between heart disease, cholesterol, and Alzheimer's disease: a review. Microsc Res Tech. 2000 Aug 15;50(4):287-90. PubMed.
  43. . Is Alzheimer's disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol. 2004 Mar;3(3):184-90. PubMed.
  44. . Vascular disease and cognitive function: evidence from the Whitehall II Study. J Am Geriatr Soc. 2003 Oct;51(10):1445-50. PubMed.
  45. . Amyloid-beta and tau serve antioxidant functions in the aging and Alzheimer brain. Free Radic Biol Med. 2002 Nov 1;33(9):1194-9. PubMed.
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  50. . Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J. 2001 Aug;15(10):1858-60. PubMed.

Other Citations

  1. the hypothesis of Aβ drainage

External Citations

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Further Reading

Papers

  1. . Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21. Nat Genet. 1998 Sep;20(1):70-3. PubMed.