The mapping of the DNA sequence of the entire human genome has resulted in enormous strides in our understanding of diseases and, in some cases, their pre-determined genetic trajectories.

Brain diseases are difficult to accurately diagnose in life. There are many overlapping features of these diseases, which can lead to extensive symptom variability among people. These dynamics are not well understood. One by-product of this complexity is the importance of genetics in the study of neurodegenerative diseases, and specifically the search for biomarkers.

A new ONDRI study1, explores the relationship of a protein (APOE) – well known to be associated with Alzheimer’s Disease – to cognitive impairment across several neurodegenerative diseases.

“When people present with a neurodegenerative disease, be it Alzheimer’s, Parkinson’s (disease) and others, we see a very heterogenous picture. Every person is different. What is causing these extensive differences within the same disease groups? As a geneticist, I have to think at least a part of these differences is due to peoples’ differing genetic makeup”, said Allison Dilliott PhD, of Western University in London, Ontario, lead author of the study.

“So, for this study, we took a known relationship — the association of APOE E4 with Alzheimer’s disease and Mild Cognitive Impairment — and tried to learn from it. We wanted to see if the presence of APOE E4 would be associated with cognitive impairment across other neurodegenerative diseases that can lead to dementia, as we might expect”, continued Dilliott.

APOE defined

Apolipoprotein E (APOE) is a gene that provides the instructions to make a protein involved in the metabolism (or processing) of fats in the body of mammals, including humans. APOE variants (or mutations) have been implicated in Alzheimer’s disease as follows:

      • APOE E3 – the ‘normal’ protein is associated with an average risk of Alzheimer’s disease
      • APOE E4 – the strongest risk factor for Alzheimer’s Disease (3-12 X normal risk)
      • APOE E2 – protective against Alzheimer’s (0.10-0.26 X normal risk2)

Methods

This research study analyzed the deep, rich ONDRI Foundational Study database. This first ONDRI study, conducted from 2013-18, included the collection of extensive, cross-platform assessment data from 520 people living with one of five diseases: Alzheimer’s disease/Mild cognitive impairment (MCI); Parkinson’s disease; Amyotrophic lateral sclerosis (ALS); Frontotemporal dementia (FTD) and Cerebrovascular disease.

ONDRI researchers segmented study participants based on their APOE genes: APOE E3, APOE E4 and APOE E2.

They then compared APOE gene status to participants’ scores on various areas (or domains) within the Neuropsychological assessment protocol. This protocol included measures of cognitive health such as memory, executive function (planning, organization etc.) and others.

Results of this comparison were then analysed, both across all the diseases, and within each disease group.

Results

Results of this study showed noticeably lower memory and visuospatial awareness scores for people who had the APOE E4 variant in their genetic code, across ONDRI participants.

Why is this Important?

Although researchers expected these results, based on the strong link between APOE E4 and Alzheimer’s disease, this is the first study to date of APOE and cognition that looked across such an extensive grouping of neurodegenerative disease diagnoses and used such detailed neuropsychology data.

Studying multiple diagnoses allowed Dilliott et al to show that the APOE E4 variant influences cognition no matter the neurodegenerative diagnosis, which is a novel finding. In addition, the rigorous and detailed study design strengthens the findings.

Adding to the complexity – correlations are pathology dependent

Among the discoveries of this research was one that was less intuitive. FTD patients with APOE E2 (the variant that is protective from Alzheimer’s disease) showed lower than average neuropsychological test scores. This was not expected and is thought to be related to the presence of Progressive supranuclear palsy (PSP), an FTD sub-type. More research is required to validate this hypothesis.

This finding highlighted the fact that cognitive performance may be individualized and pathology dependent, and that understanding the genetic component is just the start of unraveling the puzzle.

“In the end, this is a proof-of-concept study that illuminates important potential relationships between genetics and cognitive impairment, across a group of disease. We need other specialized groups to replicate and validate these results. What is exciting for us is what this means for people living with these diseases and their care partners. If we continue researching this area, in the future, when you receive a diagnosis, genetic test results could help predict your disease progression with more specificity. This would allow you to be prepared ahead of time for things to come; or could potentially allow your physician to tailor yet-to-be-developed therapeutics to slow down or even stop the progression of the disease. We are helping to pave the road for personalized medicine based on genetics” said Dilliott.

Note: ONDRI’s Foundational Study is considered relatively small by genetics standards but is very rich. Of particular importance is the depth of the neuropsychology battery of tests that were performed, allowing detailed exploration of cognitive impact.

 

Footnotes

  1. Dilliott, Allison et al,“Association of apolipoprotein E variation with cognitive impairment across multiple neurodegenerative diagnoses”, Neurobiol Aging, Septemer, 2021.
  2. Dilliott, Allison et al,“Genetic Variation in the Ontario Neurodegenerative Disease Research Initiative”, Cambridge University Press: 15 August 2019.