Molecular Psychiatry: The first large-sample clinical study shows that high polygenic risk scores for ADHD are associated with reduced cognitive risk in old age!

 *For medical professionals only

When it comes to attention-deficit/hyperactivity disorder (ADHD), most people think that it is a childhood and adolescent disorder, but in fact, ADHD does not only occur in childhood, but 11-80% of ADHD persists into adulthood, and the prevalence of ADHD over 50 years of age is 2.
18% [1,2].

Cognitive dysfunction in older ADHD patients has been shown to be very similar to the early cognitive impairment manifestations of Alzheimer's disease (AD) [3,4].

So, in older adults, is ADHD a risk factor for cognitive decline later in life? In addition, what is the relationship between ADHD and pathological changes in AD?

Due to the large time span of the onset of ADHD and cognitive decline in later life, there is a lack of large clinical cohort data, so it is difficult
to study the relationship between the two.

But recently, a team led by Tharick A.
Pascoal of the University of Pittsburgh Medical Center and Luis Augusto Rohde of the Porto Alegre Clinical Hospital in Brazil published an important finding
in Molecular Psychiatry.

They found that in older adults with normal cognitive function, especially in older populations with pre-existing β amyloid (Aβ) deposits, a genetic predisposition to ADHD could predict cognitive decline and AD pathological changes
later in life.
Specifically, higher polygenic risk scores (ADHD-PRS) for ADHD were associated with a greater risk of cognitive decline in old age (p=0.
003) [5].

Screenshot of the first page of the article

Unlike other behavioral disorders, ADHD has a genetic component, and this genetic factor is determined by a series of small genetic changes
.

To measure this genetic factor, the researchers used the ADHD-PRS score as an alternative to the diagnosis
of ADHD.
Previous studies have shown that the ADHD-PRS score is a good proxy variable because it not only represents the comprehensive genetic information of ADHD, but also reflects the genetic predisposition of ADHD, and is highly correlated with the diagnosis of ADHD and related symptoms [6,7].

To better conduct the study, the researchers used data from the AD Neuroimaging Database (ADNI), which included 212 cognitively normal older adults
.
The average follow-up was 3.
96 years, with the longest follow-up being 6 years, followed by calculating each patient's individual ADHD-PRS and matching
it to the patient's AD symptoms.

Meanwhile, to explore the relationship between ADHD-PRS scores and progressive cognitive decline and pathological changes in AD, the researchers used cognitive scores to assess cognitive function
.

In terms of AD pathological changes, the researchers used the results of magnetic resonance and positron emission tomography (PET) to assess the brain pathological Aβ protein deposition and the degree of neurodegeneration of the subjects, and for the brain tau pathological protein deposition, the researchers used phosphorylated tau181 of cerebrospinal fluid to evaluate
.

The results showed that the higher the ADHD-PRS score, the more significant the progressive decline in overall cognitive function (p=0.
003), and the ADHD-PRS score was also associated with the progressive decline of memory cognitive domain (p=0.
01).

Analysis of linear mixed-effects models showed that ADHD-PRS scores were a risk factor
for cognitive decline.

The higher the ADHD-PRS score, the faster the decline in overall cognitive function and memory cognitive domain function

In exploring the pathological changes of AD, the researchers found that higher ADHD-PRS scores were associated with overall cognitive decline (p=0.
01) and progressive decline in memory cognitive domains (p=0.
04) in subjects with brain Aβ deposition, and also with a continuous increase in cerebrospinal fluid phosphorylated tau181, and a sustained decrease in the volume of gray matter, superior frontal gyrus and superior marginal gyrus (p=0.
003).

The above results suggest that the ADHD-PRS score may be used as an indicator
to measure the risk of cognitive decline and the accelerated progression of AD-related pathological changes and brain atrophy in the elderly.

In people with brain Aβ deposition, the higher the ADHD-PRS score, the faster the decline in overall cognitive function and memory cognitive domain function

In summary, this study cleverly uses ADHD-PRS score instead of the diagnosis of ADHD, and finds that ADHD-PRS score is a risk factor for cognitive decline, which can be used as an important reference value
for clinically combining genetic and imaging information to predict cognitive decline in the elderly.

Of course, this study also has some shortcomings, such as a lack of universality, because the overall risk of ADHD genes in the study population is low, and almost all of them are white
.
In addition, there were some confounding factors that were not included in this study, such as traumatic head injury, alcoholism, and hypokinesia
.

With the construction and long-term follow-up of large clinical cohorts dedicated to the study of ADHD, in the future, perhaps one day we may be able to directly use these large clinical cohorts to further design more complete clinical studies to verify the relationship
between ADHD and cognitive decline in later life and AD.

References:

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Leffa DT, Ferrari-Souza JP, Bellaver B, et al.
Genetic risk for attention-deficit/hyperactivity disorder predicts cognitive decline and development of Alzheimer's disease pathophysiology in cognitively unimpaired older adults [ published online ahead of print, 2022 Dec 8].
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6.
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18040383

Responsible editorZhang Jinxu