Alzheimer’s: Does genetic predisposition to ADHD increase risk later in life?

  • Limited data suggest that attention deficit hyperactivity disorder (ADHD) in older adults may be linked to an increased risk of Alzheimer’s disease.
  • A recent longitudinal study showed that cognitively unimpaired older adults with a higher genetic predisposition for ADHD were more likely to experience a greater cognitive decline during the 6-year follow-up period.
  • Individuals with a genetic predisposition for ADHD and higher beta-amyloid levels were at an especially higher risk of cognitive decline and brain pathologies associated with Alzheimer’s disease.
  • These results suggest that a genetic predisposition for ADHD could be a risk factor for cognitive decline and, potentially, Alzheimer’s disease.

A recent study published in Molecular Psychiatrysuggests that older adults with a genetic predisposition for ADHD and higher levels of beta-amyloid could be at a higher risk of cognitive decline and brain changes associated with Alzheimer’s disease.

The study’s senior author, Dr. Tharick Pascoal, a neurologist at the University of Pittsburgh, told Medical News Today: “In this study, we are linking for the first-time genetic risk for ADHD with cognitive decline and the development of [Alzheimer’s disease] pathophysiology in older adults.”

However, Dr. Pascoal noted that while these results will help advance the field, caution must be exercised while interpreting these results.

“There are people who have this genetic susceptibility to ADHD and never develop ADHD symptoms, and people who do not have this genetic susceptibility and develop ADHD. This genetic susceptibility is merely a risk factor for ADHD that is not currently used in clinical practice, which further reinforces that our results have no clinical implications and should not concern patients with ADHD at this early stage.”

– Dr. Tharick Pascoal

“Therefore, it is important to highlight that more work is needed to link clinically confirmed ADHD symptoms and the development of Alzheimer’s disease dementia,” he added.

ADHD is a developmental disorder characterized by difficulty sustaining attention, impulsive behavior, and hyperactivity. These symptoms develop during childhood and may subside or disappear with age.

However, these symptoms often persist into adulthood, with studies suggesting this occurs in 11% to 80% of cases. According to a recent meta-analysis, an estimated 2.18% of individuals ages 50 years and older had ADHD.

Both adults and children with ADHD show widespread cognitive deficits. One of the characteristics of ADHD includes impairment in tasks involving executive function, which includes cognitive processes necessary for planning and controlling other cognitive functions and behaviors.

In addition, some studies based on data from national registries suggest that older adults with ADHD could be at a higher risk of mild cognitive impairment and Alzheimer’s disease. But the overlap of cognitive symptoms between ADHD and Alzheimer’s disease in older adults could lead to a misdiagnosis of ADHD symptoms as Alzheimer’s.

The association between ADHD and age-related cognitive decline remains unclear due to an absence of longitudinal studies that have tracked changes in cognitive function over time in older adults diagnosed with ADHD during their childhood.

In the present study, the researchers examined the association between genetic predisposition for ADHD and cognitive function in older adults who did not show symptoms of cognitive impairment at baseline.

They also examined how the association between ADHD and cognitive function was influenced by the accumulation of beta-amyloid, a marker for Alzheimer’s disease.

Studies have shown that genetic factors could play a significant role in the causation of ADHD, with variants of certain genes associated with an increased risk of ADHD.

In the present study, the researchers assessed genetic predisposition to ADHD by calculating the ADHD polygenic risk score, a measure of the total number of gene variants that have previously been linked to an increased risk of ADHD.

Previous studies have shown a strong correlation between the ADHD polygenic risk score and ADHD and ADHD-related traits. However, polygenic risk scores are hard to test and are often dependent on being used in a similar population to the ones used to gain data on the genetic variants linked to a train in the first place.

Abnormal accumulation of deposits of the beta-amyloid protein can be a hallmark of Alzheimer’s disease. In the present study, the researchers examined whether beta-amyloid levels at baseline influenced the progression of cognitive decline in individuals with a genetic risk for ADHD.

To assess beta-amyloid levels in the brain, the researchers used PET scans with a specialized dye.

The present study numbered 212 participants aged between 55 and 90 years who did not have a prior ADHD diagnosis. Only participants without cognitive impairment at baseline were included in the study.

The participants returned for follow-up visits at 6 months, 12 months, and then annually. The participants were administered cognitive assessment at the time of enrollment and then during selected visits.

The researchers found that a higher ADHD polygenic risk score was associated with a greater decline in general cognitive function during the six-year follow-up period. This decline in cognitive function in individuals with a higher ADHD polygenic risk score was particularly noticeable in memory-related tasks.

Participants with a greater predisposition for ADHD showed more pronounced deficits in executive function, but these deficits did not worsen over time.

A progressive decline in memory is often a sign of Alzheimer’s disease. Given the similar decline in memory, the study authors suggest that a greater predisposition for ADHD could increase the risk of dementia.

The researchers also assessed the impact of ADHD polygenic risk score and amyloid-beta levels on the development of brain abnormalities associated with Alzheimer’s disease. Specifically, they examined changes in the levels of tau protein and brain morphology during the follow-up period.

The levels of tau protein increase in the brain following the accumulation of beta-amyloid and the progression of Alzheimer’s disease. As a proxy for tau deposits in the brain, the researchers measured the levels of phosphorylated tau in the cerebrospinal fluid, the colorless fluid that surrounds the brain and the spinal cord.

Individuals with a higher ADHD polygenic risk score who also had higher beta-amyloid levels at baseline showed a greater decline in general cognitive function and memory than either factor alone.

Moreover, a combination of a higher genetic predisposition for ADHD and higher beta-amyloid levels in the brain was associated with the development of brain abnormalities observed in Alzheimer’s disease.

Specifically, these individuals showed a greater increase in phosphorylated tau levels in the cerebrospinal fluid and degeneration of brain regions involved in cognitive function during the 6-year follow-up period.

Notably, individuals with low beta-amyloid levels and a higher predisposition for ADHD or vice-versa — high beta-amyloid and low ADHD polygenic risk score — did not show a similar decline in cognitive performance or pathological changes associated with Alzheimer’s disease.

Accumulation of beta-amyloid in older individuals is associated with an increased risk of cognitive decline. The study results suggest that a predisposition for ADHD might enhance the risk of cognitive decline due to beta-amylouid accumulation.

Dr. David Merrill, a psychiatrist, and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center at Providence Saint John’s Health Center, noted that “[t]his study is important in showing that amyloid buildup in the brain alone may not result in [Alzheimer’s disease].”

“But the presence of comorbid genetic risks for conditions like ADHD may lead to amyloid-driven tau tangles and brain shrinkage. It’s ultimately these multi-factorial cascades that lead to the devastating syndrome of symptoms seen in full-blown Alzheimer’s disease,” he pointed out.

“ADHD may be an important condition to identify in older adults at risk for Alzheimer’s. What we don’t know yet is whether or not treating ADHD with stimulants or other interventions will prevent or slow [Alzheimer’s disease].”
— Dr. David Merrill

The study authors noted that further research is needed to delineate the potential association between ADHD and cognitive impairment.

The study’s first author, Dr. Douglas Leffa, a researcher at the University of Pittsburgh Medical Center, said that “[b]y following these individuals over time at various time points, we will be able to better establish an association between ADHD and Alzheimer’s disease, in addition to shedding light on factors that are enhancing the association of these two pathologies.”

“We believe that the next step is a prospective longitudinal study evaluating cognition and biomarkers of Alzheimer’s pathology in older individuals with a confirmed diagnosis of ADHD since childhood.”
— Dr. Douglas Leffa

The researchers acknowledged that their study had a few limitations. They noted that the criteria used for the enrollment of participants may have excluded individuals with a high genetic risk for ADHD.

For instance, adults with ADHD often have other co-occurring mental health disorders or cognitive deficits. The exclusion of individuals with these symptoms in the study could limit the generalizability of these results to the broader population.

The authors also noted that most of the participants in the study were white, and these findings ought to be replicated in a more diverse population.

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