30 Oct 2020

Alzheimer’s disease risk variants lurk within the genome from the beginning of life, but at what age do they start to do their dirty work on the brain? According to a study published in the October issue of Neurology Genetics, AD genetic risk factors take their toll on the hippocampus throughout the lifespan. Piecing together longitudinal data from multiple study cohorts, researchers led by Kristine Walhovd and Yunpeng Wang at the University of Oslo found that people with high burdens of polygenic Alzheimer’s risk had smaller hippocampi throughout life, from as early as young adulthood right up to the 90s.

High polygenic risk was associated with a smaller hippocampus throughout life.
Without ApoE4, this association shrank to a trend.
Each copy of ApoE4 correlated with a smaller hippocampus over lifespan.

“The most salient observation of this study is that this small but significant effect is seen in the very young,” Julie Williams wrote to Alzforum. Williams, at the U.K.’s Cardiff University, works on polygenic risk scores but was not part of this study (full comment below).

Much of this was driven by ApoE4, as the association faded to a trend when this risk factor was removed from the analysis. Together, the findings suggest that while age is a necessary ingredient for the symptoms of AD to emerge, genetic risk factors make their marks on the brain early in a person’s life.

ApoE4 is thought to affect brain structure starting in infancy, because brain scans of babies and healthy young adults have revealed smaller hippocampi in carriers (Jan 2013 news; Dec 2014 news). More recently, researchers have tied polygenic risk, which considers many genetic variants en masse, to smaller hippocampi in young adults (Foley et al., 2016).

In late life, various versions of polygenic burden have been linked to Aβ and tau pathology, cognitive decline, and age at disease onset (Jul 2016 news; Mar 2017 news; Feb 2019 news). Together, these studies hint that genetic risk sculpts the brain throughout life, though most studies have been cross-sectional, that is, considering only one age group at a time.

Walhovd, Wang, and colleagues sought to track the impact of polygenic risk across the lifespan. They strung together longitudinal brain-scan data from five Norwegian studies, which included a total of 2,690 brain scans on 1,181 participants who ranged from 4 to 95 years old. The majority were followed for an average of 11 years, with an average of nearly three years between scans. Across this “cohort,” total hippocampal volume grew from about 7,900 to 9,000 cubic millimeters between the ages of 4 and 20, then gradually shrank back to 4-year-old levels by age 70, before plummeting below 6,000 cubic millimeters by age 95.

The researchers calculated a polygenic risk score (PGS) for each participant by adding up the number of single-nucleotide variants they carried that previously had been tied to AD risk in GWAS. For their initial analysis, they even included variants weakly associated AD—with a p value less than 0.5—and weighted each depending on published effect sizes. They found that a higher PGS correlated with a lower hippocampal volume throughout the lifespan, even in the preschoolers, such that for every standard deviation uptick in PGS, the person’s hippocampal volume shrank by 36 cubic millimeters. The effect was similar for people in their 20s and 80s, but less so in middle age.

Subtracting ApoE from the PGS reduced this correlation to a trend. The trend inched closer to significance when the scientists included only those genetic variants that associated with AD with p values below 5 x 10^-8. This more exclusive PGS correlated most strongly with hippocampal volume late in life.

Finally, the researchers confirmed that ApoE4 alone influenced the size of the hippocampus throughout life. Each copy of ApoE4 docked the size of the seahorse-shaped region by an average of 107 cubic millimeters. Similar to the findings from the all-inclusive PGS, this relationship was strongest in young and late life, and weaker in middle age. The latter result could be explained by the fact that the study included fewer middle-aged participants than any other age group, the scientists speculated. Other researchers expressed concern that the lion’s share of the data in this paper came from two groups—a very young group in which hippocampal volumes were increasing, and an older group in which volumes were declining.

Overall, the findings suggest that genetic risk for AD—in particular from ApoE4—offsets hippocampal size throughout life. Without ApoE, PGS had a minimal impact on brain structure, though Walhovd and Wang hypothesize that a more significant association might emerge from larger studies. Whether living with a slightly smaller hippocampus has any bearing on cognition, or on the subsequent emergence of AD symptoms, remains uncertain.

In an editorial accompanying the paper, David Linden of Maastricht University, the Netherlands, wrote that the finding could lead to new biomarkers to identify prospective patients in preclinical stages of AD. “The biomarkers developed so far have limited clinical utility for AD prediction, and thus new multimodal approaches, incorporating both genetic risk scores and parameters of neural structure and function, should be welcome,” he wrote. Linden noted that mounting evidence supports the importance of dementia prevention in early life by way of building up cognitive reserve. “Although we are still far away from any use of hippocampal volume as a clinical proxy for cognitive reserve, the study by Walhovd et al. makes a compelling case for further longitudinal research into links between AD risk and brain structure.”—Jessica Shugart

Comments

- Julie Williams
  Cardiff University
- Posted: 30 Oct 2020
I was interested in this finding, showing that polygenic risk for AD is associated with a reduction in hippocampal volume throughout the lifespan. The most salient observation of this study is that this small but significant effect is seen in the very young.

What does this mean? This could be the manifestation of cognitive reserve. However, one could further speculate that the mechanisms which underlie Alzheimer’s polygenic risk could also underlie the processes that grow and/or maintain the capacity of the hippocampus.

Could it be that these processes also affect cognitive capacity and in turn IQ, which are known to be negatively associated with AD later in life? One may also speculate that these shared processes may implicate the role of immunity, and possibly that of microglia, in the development of both cognitive capacity in early life and the propensity to neurodegeneration later in life. These are intriguing possibilities which will need further work to unpick.

View all comments by Julie Williams

- Luiz Scofield
- Posted: 09 Nov 2020
With respect to the similarity of "each copy of APOE4" data and "all-inclusive PGS" data, and the analogy between the immune response of ages 4-20 and 70-95, I wonder whether the middle age group really does not have an intrinsic factor in its immune system that withholds the expression in microglia and astrocytes. This might also impede hippocampus tissue atrophy, rather than merely the fewer number of participants in that group accounting for the outcome.

View all comments by Luiz Scofield

Alzheimer's Risk Genes Nip at Hippocampus Throughout Life

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