1.

AD is defined by the presence of abundant extracellular amyloid plaques and intracellular tau tangles in neocortex, but cases have been reported with no tangles or with few plaques

If plaque and tangles are typical but not necessary and sufficient for AD, what is their role?

2.

Synuclein pathology can occur alongside Abeta and tau pathology

Why are some types of neurodegeneration associated with Abeta or tau pathology, while others are associated with synuclein? Why do the three types of pathology occur together in some cases?

3.

What is currently called AD has variable ages at onset, diverse symptoms, pathology and genetics

Is there a common thread?

4.

The factor most strongly correlated with AD is aging

How does aging contribute to AD pathogenesis?

5.

Women face an elevated risk of AD

Why?

6.

60 percent of people diagnosed with MCI go on to be diagnosed with AD

Can those with AD be identified while still at the MCI stage?

7.

Education level has a significant correlation with risk of AD

What is the causal relationship? Is cognitive reserve inherent or the result of education? What is the link?

8.

Cardiovascular disease and its risk factors, including ApoE4, correlate with elevated risk of AD

Does vascular disease contribute directly to AD?

9.

Metabolic disorder, diabetes, dietary factors and lack of exercise correlate with elevated risk of AD

By what mechanisms? Can intervention in these risk factors reduce the risk of AD as well?

10.

Statins, nonsteroidal anti-inflammatories and estrogen therapy are correlated in retrospective studies with reduced risk of AD

Are these real correlations or covariants? What are the mechanisms? How better to design clinical trials to test potential preventive agents?

11.

Mutations in APP, PS1 and PS2 cause early-onset familial AD (eFAD)

What do phenotypic variations among the mutations tell us? Are there other eFAD genes to be discovered?

12.

Trisomy 21 is associated with AD pathology, but studies suggest that not all Down patients develop dementia

By studying Down patients, what other mechanisms may we find that interact with APP gene dosage to produce dementia?

13.

Most but not all eFAD mutations appear to increase Abeta42, or to increase the ratio of Abeta42 to Abeta40

Do eFAD mutations cause AD through a gain of toxic function, or by the loss of an important normal function? Are there Abeta-independent effects of eFAD mutations?

14.

PS1 eFAD mutations increase tau phosphorylation through the PI3K/Akt/GSK-3 signal transduction pathway

Is this pathway relevant to AD pathogenesis?

15.

The e4 variant of ApoE increases the risk of late-onset AD, while e2 is protective

What is the pathogenic mechanism of the e4 allele?

16.

ApoE4 accounts for only some of the increased familial risk of LOAD

Are there other risk genes for LOAD, and what are they?

17.

In ApoE4 carriers, and perhaps also in eFAD mutation carriers, activation in medial temporal regions is increased decades before expected onset of any AD

What accounts for increased activation? Is this related in any way to the increased risk of AD?

18.

fMRI has identified a resting state network that overlaps with areas of pathology and dysfunction in AD brain

What does this mean for how AD develops? Could fMRI of the resting state network serve as an antecedent marker?

19.

Brain imaging studies show decreased activation in medial temporal lobe preceding the diagnosis of AD

What is causing the decreased activation, and is it playing a role in dementia?

20.

Classic pathology begins years before symptoms or detectable change in neuropsychological tests

What are the earliest pathological changes? How do Abeta and tau pathology fit in?

21.

Synaptic dysfunction and loss occur early in AD

How early? What causes this? How does synaptic loss fit into pathogenic chain. Does it precede or follow neuronal loss?

22.

Basal forebrain cholinergic neurons are selectively vulnerable in early AD

What causes this vulnerability? What downstream events are triggered by it?

23.

First detectable symptoms are impaired memory and executive function, changes in personality

What are the underlying molecular and anatomical causes for these symptoms?

24.

There is progressive degeneration starting with basal forebrain, entorhinal cortex, to hippocampal formation, parts of limbic system, association cortex, etc.

Why does degeneration follow this pattern? Is there a relationship among the affected regions?

25.

ApoE affects clearance/deposition of Abeta, rather than its production

Does ApoE exert its effect on AD risk through other mechanisms?

26.

Abeta is generated by cleavage of APP by beta- and gamma-secretase

Does the cleavage process change with aging or in AD?

27.

BACE1 levels are elevated in AD brain

Does elevated BACE1 play a role in AD pathogenesis, e.g. by driving positive feedback loop of Abeta overproduction?

28.

Abeta appears to have a normal function regulating synaptic activity

Does Abeta have other physiological functions? Does the disruption of Abeta’s normal function lead to AD?

29.

Abeta forms monomer, dimer and larger soluble oligomers, and also forms protofibrils and insoluble fibrils

Which Abeta species is/are pathogenic? Are there different toxic mechanisms associated with different Abeta species?

30.

APP is processed into a variety of cleavage products besides Abeta: AICD, C31, C100,  etc.

Do these other products of APP processing play a role in AD?

31.

F-spondin and APP are ligands of APP

What are the identities and functions of APP ligands?

32.

APP-interacting proteins include LRP, NogoR, Fe65, X11, Dab, JIP, Shc, etc.

What are their functions? Do these play a role in AD?

33.

Enzymes such as IDE and, neprilysin, ECE, MMP degrade Abeta

What is their physiological role? Are there other enzymes that degrade Abeta? Of all Abeta-degrading enzymes, which are relevant in AD brain? Which are therapeutic targets?

34.

Alzheimer tangles consist primarily of hyperphosphorylated tau, which forms paired helical filaments (PHFs)

Which kinases and phosphatases are perturbed in AD to account for PHF formation?

35.

In human brain, tau pathology precedes plaques by decades (but whether young people with tau would have developed AD is not known), but in animal models, Abeta induces tau pathology

In human AD, what is the mechanism linking Abeta and tau? Does tau contribute directly to the neurodegenerative process in AD or is it a downstream pathological change?

36.

Hyperphosphorylated tau destabilizes microtubules

Does tau play different roles in AD and FTD?

37.

Tau in AD brain exhibits N- and C-terminal truncations

Do these tau post-translational modifications play a role in AD pathogenesis?

38.

Brain inflammation/gliosis is characteristic of AD

When, how specific, how important?

39.

Oxidative stress markers are observed in AD.

When, how specific, how important?

40.

Cell cycle reactivation is observed in early AD and in APP transgenic mice

How specific to AD? Does it cause neurodegeneration? What is the mechanism?

41.

Autophagy/endosomal lysosomal changes occur in AD

When, how specific, how important?