05 Dec 2004

This report summarizes discussions and recommendations made at the fourth annual workshop on Enabling Technologies for Alzheimer's disease (AD), held in August 2004 in Bar Harbor, Maine. Academic and industry scientists from inside and outside the field of Alzheimer disease research met with foundation representatives and an administrator from the National Institute on Aging. Their goal was to identify knowledge gaps that are limiting progress in AD diagnosis and therapy, as well as strategies to bridge these gaps. On the first day, participants reviewed current knowledge on synaptic and axonal dysfunction in AD, and on protein misfolding in neurodegenerative diseases. The second day saw discussion of imaging frontiers in AD diagnosis and treatment monitoring.

Participants generated a table summarizing what findings have achieved consensus across the field and on which issues researchers still disagree. The points of discussion and final recommendations presented in this report emerged during the discussions and do not reflect an order of priority or the unanimous views of all participants. We'd love to hear your thoughts. Please send us your comments.

What We Know	What We Don't Know
APP's sequential cleavages. APP and PS mutations that increase Abeta42 cause familial AD	What regulates the secretases?
APP cleaves into other fragments, including AICD, C31 (via caspase cleavage), C100, etc.	What does APP do? What does Aβ do? What about the other cleavage products?
A PS1 mutation causes a frontotemporal dementia without Aβ deposition	Do PS1 and APP mutations cause dementia by pathways other than Aβ?
PS1 has many other substrates besides APP	Do these other PS targets contribute?
	Are there other enzymes that generate Aβ?
	What are the identities and functions of APP-interacting proteins?
	APP ligands? (Other than F-spondin and APP.)
ApoE only proven LOAD risk factor, affects age of onset.	Other late-onset genes (model suggest 4-6 others exist)
ApoE affects not production but clearance/deposition of Aβ.	Precise mechanism of ApoE effect on Aβ.
Enzymes can degrade Aβ.	Role of IDE, neprilysin in AD; identity/function of other players in Aβ degradation.
Aggregation of tau occurs, is damaging.	Mechanism of link between Aβ and tau
Abnormal tau destabilizes microtubules.	Details of tau toxicity.
Synaptic dysfunction and loss occurs.	How and when? Where does it fit into the cascade of AD pathology?
First symptoms are impaired memory and executive function, change in personality.
Classic pathology begins years before symptoms or detectable change in neuropsychology tests.	Are there changes that precede Aβ pathology?
Hippocampal formation, parts of limbic system begin to atrophy, whole brain shrinks	Which cortical areas are affected first?
Changes in brain imaging, decreased activation in medial temporal lobe	Relationship between medial temporal and posterior areas.
Early onset disease is variable, late-onset disease is predictable	Is AD one disease or many?
Inflammation plays a role	When and how important?
Cell cycle reactivation	Ditto
Autophagy/endosomal lysosomal changes	Ditto
Gliosis	Ditto
Lifestyle factors protect but no agreement on which ones. Candidates include activity, education, diet, and antioxidants.
Risk factors: aging, head trauma	Why is aging a risk factor?

 

—Gabrielle StrobelJune Kinoshita

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