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Article from Dr. JoAnne McLaurin, PhD.  Senior Scientist Sunnybrook Research Institute 2020

In 2019-2020, we have advanced one specific program more than other ongoing studies that I have previously talked about at Cryptic Rite functions. I will thus highlight our novel findings in understanding what drives the progressive loss of cognitive function in Alzheimer’s disease patients over the course of the disease and why clinical trials keep failing.


Failure of Alzheimer’s disease (AD) clinical trials, primarily those targeting amyloid, to improve or stabilize cognition has led to the need for a better understanding of the driving forces behind cognitive decline in the presence of active disease processes. A defining feature of AD is progressive accumulation of amyloid and tau pathology in the brain that ultimately leads to cognitive decline. Neuronal loss progresses across specific brain regions that interconnect with each other and is mirrored by symptomatic presentation with mild memory loss typically occurring first, followed by deficits in activities of daily living and executive function, and eventually dementia. Hippocampal dysfunction has long been thought to drive memory impairments in AD. Recently this focus has shifted to include the entorhinal cortex, a region which provides input into the hippocampus, and is affected early in AD progression. The hippocampus regulates behavioural responses to a changing environment through circuit modulatory effects. These behaviours include pattern separation and executive function as assessed by cognitive flexibility. Pattern separation involves the disambiguation between learned and novel stimuli into distinct neuronal networks, whereas executive functions consist of multiple high-level cognitive processes that drive rule generation and selection. These processes are essential to normal human behavior, and are disrupted in AD and AD models.


Thus, we utilized a rat model which recapitulates the salient hallmarks of AD pathology observed in patient populations (amyloid, tau inclusions, frank neuronal loss, and cognitive deficits). We examined the contribution of combined pathologies to cognitive function, and the effect of amyloid-attenuation in disease-bearing rats. Attenuating amyloid in disease-bearing rats rescued pattern separation and executive function. Interestingly, neither activities of daily living were rescued by attenuating amyloid. To understand the pathological correlates leading to behavioural rescue, we examined the neuropathology and neuronal signature of the hippocampus. Amyloid attenuation reduced hippocampal pathology and promoted resilience in adult hippocampal neuronal function, via improvements in coupling between neuronal signals. To investigate mechanisms underlying the lack of effect on spatial memory deficits, we next examined the entorhinal cortex, a brain region whose input to the hippocampus is required for spatial memory. Reduction of amyloid in the entorhinal cortex had no effect on pathology or entorhinal-hippocampal neuronal network communication. Thus, rescue or not of cognitive function is dependent on each specific brain region’s progression of amyloid, tau and neuronal network dysfunction. Our data support the necessity for discovering early biomarkers to accurately stage disease progression, and that the use of amyloid-targeted therapeutics for clinical AD patients may be more efficient in combinatorial treatment approaches. We are now investigating the effects of combination treatments in our rodent models of AD to prove that combinations of drugs will be effective treatment options, as is seen in other complex diseases.


We continue to work on how comorbid diseases contribute to the risk of dementia and probe for novel ways to treat both the peripheral effects of comorbidities and the effects within the brain.

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