15 Aug 2014

Neural circuits falter in the earliest stages of Alzheimer’s Disease, regardless of when or why it strikes, according to a paper in the July 28 JAMA Neurology. A large cadre of researchers led by Beau Ances at Washington University in St. Louis compared changes in brain connectivity in people at risk for sporadic, late-onset AD with that in people who harbor causal mutations. As cognition declined, communication broke down both within and between neural networks in both versions of the disease. The results support the notion that the deterioration of neural networks underpins both sporadic and autosomal-dominant AD, and suggest that changes in connectivity may one day serve as useful biomarkers, Ances told Alzforum.

“This study highlights the need for direct comparisons between biomarkers in ADAD and sporadic AD,” Adam Fleisher of Eli Lilly and Company in Indianapolis wrote in an editorial (Fleisher 2014). “It is a step in the right direction toward the elusive goal of defining surrogate biomarker endpoints for therapeutic clinical trials, particularly secondary prevention efforts.”

Only a small fraction of people with AD suffer from the autosomal-dominant form of the disease (ADAD), which is caused by mutations in the genes encoding amyloid precursor or presenilin proteins. Sporadic disease accounts for the lion’s share of AD cases, and is caused by a smattering of genetic and environmental risk factors that promote late-onset AD (LOAD). How well the two forms of the disease mirror each other in terms of progression affects the way scientists interpret biomarkers and design potential treatments for each one.

Changes in neural connectivity are gaining traction as markers of AD progression, but whether the circuits collapse similarly in ADAD and LOAD is unknown. In the context of people at risk for LOAD, researchers previously reported breakdown of several networks as people age or become cognitively impaired. These include the default mode network (DMN), the dorsal attention network (DAN), the salience network (SAL), the sensorimotor network (SMN), and the executive control network (CON) (see Jul 2012 news story). Separate studies reported breakdowns in the DMN in ADAD or LOAD as cognition declined (see Aug 2013 news story). The DMN is an interconnected collection of brain regions that remains “on” when the mind wanders and is the first to be affected by Aβ plaques. Normally the DMN and DAN networks oppose each other, but in people at risk for LOAD who tested positive for AD biomarkers, the DAN failed to shut down when the DMN was on.

For the current study, Ances wanted to pull all of the pieces together, looking at functional connectivity across all five networks, in populations harboring ADAD mutations as well as those at risk for LOAD. Co-first authors Jewell Thomas and Matthew Brier and colleagues drew from two cohorts at risk for ADAD and LOAD, respectively: the international Dominantly Inherited Alzheimer’s Network (DIAN), and an aging cohort at the Knight Alzheimer Disease Research Center at Washington University in St. Louis. The researchers took resting-state functional connectivity MRI scans of 79 people in the DIAN group (including 25 family members who did not carry a causal mutation), and 444 people in the Knight group (including 343 cognitively normal people). The researchers measured cognitive function using the Clinical Dementia Rating (CDR) scale, and correlated these scores with connectivity data. In both the ADAD and LOAD-risk cohorts, mild signs of cognitive deficits correlated with decreased functional connectivity in the DMN, DAN, and CON networks. Neural circuitry problems worsened more sharply with cognitive decline in the ADAD group than in the LOAD group.

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Researchers measured resting state functional connectivity within five neural networks (color-coded), as well as the strength of the connections between them in people at risk for different forms of AD. *[Image courtesy of Thomas et al., JAMA Neurology © 2014, American Medical Association.]*

The researchers also found a similar breakdown in connections between networks. Normally the DMN shuts off when the DAN turns on, but in both the ADAD and LOAD groups this distinction blurred as cognition declined. The DMN and SMN also failed to toggle back and forth as cognition declined in both cohorts, and in the LOAD cohort, the same was true for the CON and SMN. “The networks are just weakly flipping back and forth,” Ances said.

The researchers observed a trend toward decreased functional connectivity in cognitively normal ADAD mutation carriers as they inched closer to their expected year at onset, which is based on when their family members started showing cognitive symptoms. The trend suggests that disconnections in neural circuitry may closely precede the onset of dementia, Ances said (see video), and serve as markers of progression. That could supplement other biomarkers, such as CSF-Aβ, that change decades prior to symptom onset but don't predict when a person may become symptomatic. That connectivity in people with ADAD and LOAD deteriorates similarly adds support to the idea that therapies that work for one, could work for the other, Ances said.

Functional connectivity measurements are easier and cheaper to perform than amyloid PET scans, and do not involve exposure to radiation, he added. Should functional connectivity be used as a primary readout for disease progression in clinical trials? “No,” Ances said, “but it may be able to tell us which networks are changing in response to medications, and perhaps one day we’ll be able to tailor our medications to specific networks.”—Jessica Shugart

Neural Circuitry Goes Haywire in Both Sporadic and Familial AD

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