Jack de la Torre

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.

View Transcript of Live Discussion — Posted 23 August 2006

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

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:

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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

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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

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