Edited by: George Perry, University of Texas at San Antonio, United States
Reviewed by: Samuele Cortese, University of Southampton, United Kingdom
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In this review, we undertake a critical appraisal of eight published studies providing first evidence that a history of attention-deficit/hyperactivity disorder (ADHD) may increase risk for the later-life development of a neurodegenerative disease, in particular Lewy body diseases (LBD), by up to five-fold. Most of these studies have used data linked to health records in large population registers and include impressive sample sizes and adequate follow-up periods. We identify a number of methodological limitations as well, including potential diagnostic inaccuracies arising from the use of electronic health records, biases in the measurement of ADHD status and symptoms, and concerns surrounding the representativeness of ADHD and LBD cohorts. Consequently, previously reported risk associations may have been underestimated due to the high likelihood of potentially missed ADHD cases in groups used as “controls”, or alternatively previous estimates may be inflated due to the inclusion of confounding comorbidities or non-ADHD cases within “exposed” groups that may have better accounted for dementia risk. Prospective longitudinal studies involving well-characterized cases and controls are recommended to provide some reassurance about the validity of neurodegenerative risk estimates in ADHD.
Attention-deficit hyperactivity disorder (ADHD) is a psychiatric disorder beginning in childhood that is characterized by core symptoms of inattention, impulsivity, and hyperactivity (Biederman and Faraone,
ADHD may persist into later life as well. Roughly 3% of adults over age 50 suffer from significant symptoms of attention-deficit/hyperactivity disorder (ADHD; Michielsen et al.,
Some data have suggested a link between ADHD and neurodegenerative disease, which appears to be specific to Lewy body diseases (LBD; Baumeister,
In the last 15 years, eight published studies have suggested that ADHD may be a risk factor for incident neurodegeneration (Walitza et al.,
Summary of eight studies investigating relationships between antecedent ADHD and later-life neurodegenerative diseases.
Walitza et al. ( |
Golimstok et al. ( |
Curtin et al. ( |
Fluegge and Fluegge ( |
Tzeng et al. ( |
Fan et al. ( |
Du Rietz et al. ( |
Zhang et al. ( |
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To quantify ADHD symptoms that preceded PD onset, accounting for exposure to psychostimulants. | To determine whether ADHD symptoms precede the onset of clinical DLB. | To investigate whether antecedent ADHD is linked to increased incidence of BG&C diseases. | To determine the role of antecedent ADHD in dementia risk. | To clarify the association between adults with ADHD and the risk of dementia. | To determine whether PD patients exhibit a greater propensity for prior ADHD than controls. | To investigate associations between ADHD and a wide range of physical health conditions across adulthood. | To evaluate cross-generation familial aggregation of ADHD and Alzheimer’s Disease/any dementia. | |
88 healthy controls 88 PD (43 early-onset) | 149 healthy controls 109 DLB 251 AD | 158,790 controls 31,769 ADHD | No sample sizes specified other than “162 state-year observations” | 2,025 controls 675 ADHD | 10,726 controls 10,726 PD | 4,789,799 cases; 61,960 (1.29%) had lifetime prevalence of ADHD | 2,132,929 index persons and their relatives (parents, grandparents, and aunt/uncles) | |
WURS-k total score as the primary outcome of interest (also reported WURS-k ≥30 for clinical childhood diagnosis). | WURS ≥32 for retrospective diagnosis of childhood ADHD; DSM-IV criteria for diagnosis of adult ADHD. | ICD-9 codes 314.00 and 314.01 (ADD without and with hyperactivity), 314.1 (hyperkinesis with developmental delay), 314.2 (hyperkinetic conduct disorder), 314.8 and 314.9 (other or unspecified hyperkinetic manifestations) | ICD-9 code 314.01 (ADD with hyperactivity). | ICD-9 codes 314 (includes ADD with and without hyperactivity, hyperkinesis with developmental delay, hyperkinetic conduct disorder, other or unspecified hyperkinetic manifestations). | ICD-9-CM code 314.0 (ADD without and with hyperactivity). | ICD-9 codes 314 (includes ADD with and without hyperactivity, hyperkinesis with developmental delay, hyperkinetic conduct disorder, other or unspecified hyperkinetic manifestations) and ICD-10 codes F90 (includes disturbance of activity and attention, hyperkinetic conduct disorder, other or unspecified hyperkinetic disorder) or ADHD medication prescription. | ICD-9 codes 314 (includes ADD with and without hyperactivity, hyperkinesis with developmental delay, hyperkinetic conduct disorder, other or unspecified hyperkinetic manifestations) and F90 (includes disturbance of activity and attention, hyperkinetic conduct disorder, other or unspecified hyperkinetic disorder). | |
Clinical diagnosis of PD. | Probable AD based on NINCDS/ ADRDA criteria (McKhann et al., |
ICD-9-CM codes 332.0 (PD), 332.1 (secondary parkinsonism), 333.0 (other degenerative basal ganglia diseases), 333.1 (essential and other specified forms of tremor). | ICD-9 codes 331.0 (AD) and 331.82 (LBD). | ICD-9-CM codes 290.0 (senile dementia), 290.10–290.13 (presenile dementia, uncomplicated or with delirium or delusional or depressive features), 290.20–290.21, 290.3 (senile dementia with delusional or depressive features or delirium), 290.4, 290.41–290.43 (vascular dementia, uncomplicated or with delirium or delusional or depressed mood), 290.8–290.9 (other or unspecified senile psychotic condition), and 331.0 (Alzheimer’s disease). | ICD-9-CM code 332.0 (PD) with at least 3 outpatient visits or hospital admissions and at least one PD medication. | ICD-8 codes 342.00 (PD), 342.08–342.09 (other defined or unspecified parkinsonism); ICD-9 codes 332.0 (PD), 332.1 (secondary parkinsonism), 333.0 (other degenerative diseases of the basal ganglia); ICD-10 codes G20 (PD), G21.2 (secondary parkinsonism due to other external agents), G21.3 (postencephalitic parkinsonism), G21.8-G21.9 (other defined or unspecified secondary parkinsonism), G23.1 (progressive supranuclear ophthalmoplegia), G23.2 (striatonigral degeneration), G23.8 (other specified degenerative diseases of basal ganglia), G23.9 (unspecified degenerative disease of basal ganglia), G25.9 (unspecified extrapyramidal and movement disorder). | AD: ICD-7 codes 304 (senile psychosis), 305 (presenile psychosis); ICD-8 code 290 (dementia senile and presenile); ICD-9 codes 290A (senile dementia), 290B (presenile dementia, onset < 65 years), 290X (dementia associated with aging, unspecified), 331A (presenile and senile degeneration of the Alzheimer’s type); ICD-10 codes F00 (dementia in AD), F03 (unspecified dementia), G30 (AD). Other dementias: ICD-7 code 306 (psychosis with arteriosclerosis of the brain); ICD-8 codes 293.0 (psychosis of central nervous system with cerebral arterioles), 293.1 (psychosis of central nervous system without cerebrovascular disease); ICD-9 codes 290E (multi-infarction dementia), 290W (other specified age-related dementia), 294B (dementia in somatic disease classified elsewhere), 331B (Pick’s syndrome), 331C (senile degeneration of the brain of unspecified type), 331X (cerebral degeneration, unspecified); ICD-10 codes F01 (vascular dementia), F02 (dementia in other diseases classified elsewhere), F05.1 (delirium with underlying dementia), G31.1 (senile degeneration of brain, not elsewhere classified), G31.8 (other specified degenerative diseases of nervous system). | |
No participant was taking stimulant medication. No other covariates considered. | Patients matched to controls by age, sex and education. No participant was taking stimulant medication. No other covariates considered. | Adjusted for sex, age, race/ethnicity, psychotic conditions, tobacco use. | Adjusted for diabetes (clinical classification software diagnostic category 50) and obesity (not otherwise specified, code 278.00). | Adjusted for age, sex, comorbidities, geographical area, urbanization, income. | Adjusted for Charlson Comorbidity Index. | Adjusted for sex and birth year of both relatives (to account for different follow-up lengths). | Adjusted for birth year of index persons and of relatives, and sex of index persons and of relatives. | |
On the WURS-k, group differences on the ‘Attention deficit/hyperactivity’ subscale (0.8 ± 0.8 in patients and 0.6 ± 0.6 in controls, |
ADHD was significantly more frequent in DLB (47.8%) than in AD (15.2%) or controls (15.1%). ORLBDvsControl = 5.1 [95% CI = 2.7–9.6]. | Incident BG&C was significantly more frequent in ADHD (0.52%) than in controls (0.19%). aHRBG&C = 2.4 [95% CI = 2.0–3.0]. Incident PD was significantly more frequent in ADHD (0.18%) than in controls (0.06%). aHRPD = 2.6 [95% CI = 1.8–3.7]. When including only ADHD not taking stimulant medication: aHRBG&C = 1.8 [95% CI = 1.4–2.3] and aHRPD = 2.3 [95% CI = 1.5–3.5]. | IRRLBD = 1.16 [95% CI = 1.01–1.32] adjusted for diabetes. IRRLBD = 1.06 [95% CI = 0.95–1.18, n.s.) adjusted for diabetes and obesity. | Incidence of dementia was higher in ADHD (5.48%) than in controls (4.0%). aHRDementia = 4.01 [95% CI = 2.53–6.36]. aHRAD = 0.52 [95% CI = 0.06–4.53, n.s.]. aHRVaD = 6.28 [95% CI = 2.71–25.85]. aHROtherDementia = 5.22 [95% CI = 3.13–8.72]. | Prior diagnosis of ADHD was more frequent in PD (0.13%) than in controls (0.05%). Adjusted OR = 3.65 [95% CI = 2.26–10.50]. | Individuals with ADHD had increased risk of all physical conditions except rheumatoid arthritis. ORPD = 1.50 [95% CI = 1.08–2.09]. ORDementia = 2.44 [95% CI = 1.86–3.19]. | Higher risk of AD and dementia in family members of index persons with ADHD compared to family members of index persons without ADHD. Parents: aHRAD = 1.55 [95% CI = 1.26–1.89]). aHRAnyDementia = 1.34 [95% CI = 1.11–1.63]. Grandparents: aHRAD = 1.11 [95% CI = 1.08–1.13]. aHRAnyDementia = 1.10 [95% CI = 1.08–1.12]. |
A recent review (Baumeister,
The use of health administrative data enables population-level analyses, improves generalizability of results, and minimizes referral bias (Benchimol et al.,
In four studies (Curtin et al.,
There is also considerable variability in the disorders encompassed by the diagnostic codes used to define LBD (
There is also considerable worldwide variability in the use of the ICD versions, with some countries implementing “clinical modifications” that modify ICD codes according to country-specific needs, e.g., ICD-9-CM and ICD-10-CM in the US, or ICD-10-CA in Canada (Otero Varela et al.,
The extent to which ICD codes actually correspond to the presence of a disease or disorder has been examined in multiple studies of ADHD (e.g., O’Malley et al.,
Error rates in ICD coding for ADHD may also be high, in part because clinicians seldom actually establish that all ADHD diagnostic criteria are present, even when an ICD code of ADHD is recorded consistently across visits (Daley et al.,
The selection of controls in these studies does not include systematic assessment to rule out ADHD. This is problematic because, especially in adults, ADHD is underdiagnosed (Newcorn et al.,
Lastly, it should be noted that two studies in this review used data from either inpatient hospitalization visits (Fluegge and Fluegge,
In two case-control studies of interest (Walitza et al.,
In quantifying childhood symptoms, neither study considered potential confounding factors that may have accounted for symptomatology. It is crucial to ascertain that inattention/hyperactivity in childhood is truly attributable to ADHD and not to other factors such as traumatic brain injury (Lee et al.,
In a smaller case control study (Golimstok et al.,
In examining neurodegenerative disease outcomes, some studies included early-onset disease cases (Walitza et al.,
No studies accounted for attrition, despite acknowledgements that at least some participants withdrew from initial eligible samples (Tzeng et al.,
In two studies (Walitza et al.,
We conducted a formal evaluation of the quality of the eight studies in this review using the Newcastle-Ottawa Scale (Wells et al.,
Evaluation of the quality of the eight studies in this review using the Newcastle-Ottawa Scale.
Case-control studies | |||||||||
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Is the case definition (ND outcome) adequate? | Representativeness of the cases | Selection of controls | Definition of controls | Comparability of groups | Ascertainment of exposure | Same method of ascertainment for cases and controls? | Non-response rate | Overall quality | |
Walitza et al. ( |
Known medical diagnosis |
No; sample was enriched for early-onset PD | Community controls |
No history of PD |
Groups not matched, and no adjustment for confounds | Symptom count in childhood based on retrospective self-report | Yes |
Same in both groups (0%) |
5/9 |
Fan et al. ( |
ICD 9-CM code of PD with ≥3 outpatient visits or hospital admissions and receiving PD medication | Yes |
Same sample as cases, but unclear if controls constitute a hospitalized sample | Figure 1 indicates controls were ‘subjects without PD’ |
Groups matched on sex, age, and index date; analyses used Charlson Comorbidity Index |
ICD-9-CM code of 314.0 (ADD with and without hyperactivity) | Yes |
Same in both groups (0%) |
6/9 |
Golimstok et al. ( |
Probable AD based on NINCDS/ADRDA criteria (Lindemann et al., |
Yes |
Same sample as cases, but unclear if controls constitute a hospitalized sample | No history of ND |
Groups matched on sex, age, geographic area, and education |
DSM-IV criteria ascertained by clinician blind to case/control status |
Yes |
Same in both groups (0%) |
8/9 |
Curtin et al. ( |
Included several non-ADHD hyperkinetic syndromes | Drawn from the same population as the exposed cohort |
ICD 9-CM codes linked to Utah Population Database |
Patients were excluded if BG&C disorders were present prior to an index ADHD diagnosis or before age 21 |
Matched on sex and birth year; analyses controlled for race, ethnicity, psychotic conditions and tobacco use |
ICD 9-CM codes linked to Utah Population Database |
1996–2016 (median follow-up was 21 years) |
2.5% cases lost to follow-up vs. <1% controls; statistical models included a competing risk of death |
8/9 |
Fluegge and Fluegge ( |
Only considered ADD with hyperactivity (not inattentive presentation); only considered hospitalization for ADHD | Drawn from the same population as the exposed cohort |
ICD 9-CM codes linked to the Healthcare Cost and Utilization Project |
No | Not stated whether cohorts were comparable; analyses adjusted for age, diabetes and obesity |
ICD 9-CM codes linked to the Healthcare Cost and Utilization Project |
Ten-year lagged measure |
Data were drawn from the HCUP, which includes |
7/9 |
Tzeng et al. ( |
Included several non-ADHD hyperkinetic syndromes; exposed cohort restricted to inpatients, or those with ≥3 outpatient visits within 1 year | Drawn from the same population as the exposed cohort |
ICD 9-CM codes linked to the National Health Insurance Program |
Participants excluded if dementia was present before tracking began or before an ADHD diagnosis |
Matched on sex, age, geographic area and urbanization of residence, comorbidities, and income |
ICD 9-CM codes linked to the National Health Insurance Program |
2000–2010 |
No information provided | 7/9 |
Du Rietz et al. ( |
Included several non-ADHD hyperkinetic syndromes or individuals prescribed ADHD medication | Siblings, half-siblings, and family members, drawn from the same population as the exposed cohort |
ICD-9 and ICD-10 codes linked to the National Patient Register |
No, exposures and outcomes were treated as lifetime presence or absence (no consideration of onset timing) | Stratified by sex, and birth year of relatives to adjust for follow-up lengths |
ICD-9 and ICD-10 codes linked to the National Patient Register |
All participants followed from birth until 2013, range 18–81 years (mean = 47 years) |
Data were drawn from the Total Population Register (i.e., includes |
7/9 |
Zhang et al. ( |
Included several non-ADHD hyperkinetic syndromes or individuals prescribed ADHD medication | Drawn from the same population as the exposed cohort |
ICD-9 and ICD-10 codes linked to the National Patient Register |
Not applicable, as the aim was to evaluate dementia in biological relatives, not individuals with ADHD themselves. | Analyses adjusted for index persons’ and relatives’ birth year and sex |
ICD-7, ICD-8, ICD-9, and ICD-10 codes linked to the National Patient Register |
All relatives followed until dementia onset, death, migration, or end of study (median 8–25 years) |
Data were drawn from the Total Population Register (i.e., includes |
7/8 |
Despite these strengths, two major components required to draw strong conclusions from these studies—ascertainment of exposure (ADHD) and representativeness of the exposed cohort—were flawed across almost all studies: including non-ADHD hyperkinetic syndromes or restricting the sample to those with numerous outpatient visits or hospitalizations results in samples that do not likely represent most ADHD cases, and non-exposed cases were also not systematically assessed to rule out ADHD. Likely, these methodological issues result in a conservative estimate of true effects; that is, without the “noise” generated by the inclusion of non-ADHD cases in the exposed group and potentially missed ADHD in the non-exposed group, associations between exposure and outcome may be even stronger. A second possibility is that the inclusion of non-ADHD cases in the exposed group is driving observed effects. As previously noted, many non-ADHD hyperkinetic disorders—which were included in the exposed cohort in four of the five cohort studies (Curtin et al.,
These studies present first evidence of a link between ADHD and risk of dementia, specific to LBD. Strengths include well-powered analyses and extensive follow-up periods (>10 years) in most studies. However, six (Curtin et al.,
These studies provide tentative support for ADHD as a potential risk factor for later development of a neurodegenerative disease. Due to the methodological limitations and biases we have identified, we argue that the true association between ADHD and neurodegeneration is not yet identifiable. The sources of biases identified here should be considered in future studies to ascertain the true relative risk of neurodegeneration in patients with ADHD. Accurate and systematic diagnoses of ADHD and neurodegeneration are needed.
BC conceptualized the work. SB, MS, and BC made substantial contributions to the critical analysis and interpretation of data. SB, MS, and BC wrote initial drafts of the manuscript. SB and BC wrote the final draft. All authors revised it critically for important intellectual content, approved the version to be published, and agree to be accountable for all aspects of the work.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
This work was supported by an Eyes High Postdoctoral Match-Funding Fellowship to SB and by a Canada Research Chair to BC.