3. Genetic effects Apolipoprotein E (APOE) ??4 is the most important known genetic risk factor for typical late-onset AD. The lifetime risk HTC of developing AD is increased and the age of onset of the disease is decreased with increasing number of APOE ??4 alleles [64]. Studies have shown that APOE ??4 carriers and non-carriers have dissimilar functional connectivity networks in younger adults [65] as well as older adults [51,66]. In a recent study, Sheline and colleagues [67] showed that there is altered connectivity in APOE ??4 carriers before the onset of amyloid plaque formation, suggesting that the genetic effect of APOE is seen even before any pathological changes. These studies suggest that it is important to take into account the functional architecture differences due to genetics. 4.

Amyloid deposition and functional connectivity in Alzheimer’s disease Amyloid deposition is widely believed to be an early process in AD and by itself does not directly cause clinical symptoms [68]. Pittsburgh compound B (PIB) PET scans have commonly been used as a surrogate for amyloid deposition [69] in recent fMRI AD studies. Recent literature has consistently shown that there is a disruption of functional connectivity (especially, DMN) in subjects with amyloid deposition but no cognitive impairment [43,44,49,70-72]. However, whether these early changes to the functional architecture are a compensatory mechanism to amyloid toxicity or a cause of amyloid deposition needs to be further investigated [73]. 5.

Measuring efficacy of therapeutics At present, AD biomarkers have not yet been validated as surrogate endpoints for regulatory purposes and therefore Carfilzomib cannot be used as the primary indicators of efficacy. However, there is a search for biomarkers that are non-invasive (to use for serial measurements) as well as sensitive (to perform clinical trials with smaller sample sizes). fMRI has always been viewed as a potential candidate since it can capture subtle pharmacodynamic effects on brain connectivity. TF-fMRI is of particular interest since its effect size is 2.4 times better than that of encoding-associated fMRI techniques in distinguishing risk groups and much easier to set up on clinical scanners because no additional specialized hardware or software is needed [66]. A recent study showed that TF-fMRI can detect the effect of symptomatic treatment for moderate AD over 6 months [74].

6. Differential diagnosis of dementias Given that pathology does not always map onto the clinical expression of the disease and has considerable clinical heterogeneity, biomarkers (such as TF-fMRI) that can provide information about the various functional networks may aid in the differential diagnosis of dementia types. Functional deactivation contain [75] and rs-fMRI differences [76] have been shown to be different between subjects with dementia with Lewy bodies and AD.