We report, to our knowledge for the first time, that the offspring of older fathers show impairments on a range of neurocognitive tasks during infancy and childhood. The pattern of findings was relatively consistent across ages and across neurocognitive domains, with near-linear declines found in most of the measures. When the data were examined with a more stringent definition of cognitive impairment (scores in the lowest 10%), a significant relationship between APA and impaired neurocognition was found for three of the six outcome variables, with trend level associations found for the remaining three variables. These findings persisted after adjustment for a range of socioeconomic variables and for parental mental health. In striking contrast to the findings for APA, the association between advanced maternal age and performance on neurocognitive tasks was in the opposite direction.
The findings differ somewhat from those reported by Malaspina et al. [35
], who reported on four different measures related to cognitive ability in teenagers (age 16–17y). In that study the offspring of both younger (<20 y) and older fathers (>40 y) had impaired neurocognitive performance compared to those with fathers in the other age strata. However, differences between the Malaspina et al. study and the current study with respect to the psychometric measures and the age of the offspring make direct comparisons difficult. As expected, the current study also identified an association between advanced maternal age and superior performance on the neurocognitive tests, in keeping with some [36
] but not all studies [35
The association between APA and reduced neurocognitive ability may have important implications for clinical outcomes previously linked to APA. While not all individuals with autistic spectrum disorders have impaired intelligence, many have specific learning disabilities and/or intellectual handicap [55
]. With respect to schizophrenia, systematic reviews and meta-analyses have shown a reliable, medium-sized impairment in premorbid intelligence associated with this disorder [56
]. For example, Woodberry et al. [57
] reported that years before the onset of psychotic symptoms, individuals who later developed schizophrenia had IQ scores that, on average, were approximately one-half of a standard deviation below that of healthy comparison participants. Consistent with these findings, a systematic review of the antecedents of schizophrenia based on prospective birth cohorts [58
] provided robust evidence that individuals who later develop schizophrenia show deviation during childhood on a range of cognitive measures related to intelligence, motor development, speech and language, and educational outcomes. In particular, cohort members who later developed schizophrenia, as a group, achieved lower scores on intelligence tests in childhood and adolescence than their peers [59
The findings from this study linking APA and impaired cognition may be best conceptualized within the notion of impaired cognitive reserve [62
]. Just as superior cognitive capacity appears to provide a buffer against dementia [64
], subtle APA-related impairments in neurocognitive ability may contribute to an increased risk of a diverse range of adverse neurological and neuropsychiatric health outcomes.
The study has several caveats. Nonrandom sample attrition and missing data may influence the generalisability of the findings [41
]. Those with missing data on paternal age were more likely to be lost to follow-up. It will be important to examine the variables of interest in cohorts with optimal participant retention and minimal missing data. More importantly, the cohort members were born in the United States during the 1960s, thus the generalisability of the findings with respect to more contemporary cohorts needs to be examined. While it is feasible that various economic and psychosocial factors that can influence childhood developmental trajectories may have changed in recent decades, there is no reason to suspect that the putative biological processes linking APA and adverse health outcome would have varied over this time frame. Finally, it is important to note that these analyses investigated neurocognitive outcomes only until age 7 y, and it is feasible that the offspring of older fathers “catch up” during later childhood. How the subtle neurocognitive features associated with APA translate into later educational and mental health outcomes across the lifespan remains to be determined.
With respect to the mechanism of action underpinning these findings, several hypotheses warrant further scrutiny. While twin studies have demonstrated that cognitive ability and brain structure are heritable [66
], studies based on sibships within the CPP have also confirmed that socioeconomic factors play a role in mediating the heritable aspects of intelligence [68
]. With respect to paternal age, a broad range of socioeconomic factors improve with increasing age, thus most commentators believe that the offspring of older parents would have better access to health and educational services compared to the offspring of younger parents (who tend to have lower education and poorer income) [69
]. For example, Fergusson and Lynsky [38
] found that offspring of younger mothers tended to be born into relatively poorly educated and socially disadvantaged families. These authors commented that children born to young mothers were exposed to less nurturing and more changeable home environments. One would expect that such mechanisms would also operate with respect to paternal age. Clearly, our findings linking APA with impaired neurocognitive development cannot be readily explained by these social mechanisms.
Mechanisms related to the development of the male germline warrant consideration [70
]. Each time the cell divides, the replication of the genome introduces the possibility of copy error mutations. In humans it has been confirmed that sperm from older men have significantly more mutations [2
]. Levels of DNA proofreading and repair enzymes also decline as a function of APA [16
] and DNA fragmentation increases [73
], further compromising the integrity of gene replication. Apart from genetic changes (i.e., changes in DNA basepair sequence), APA may also involve abnormal epigenetic mechanisms [74
Unravelling the molecular mechanisms underlying the association between APA and adverse health outcomes will be a substantial task for the biomedical research community. The precise location and nature of these mechanisms will probably vary substantially from offspring to offspring. It is unlikely that they will “map” neatly to a few loci, nor probably to one mechanism (e.g. genetic, epigenetic). With respect to genetic mechanisms, these may include single nucleotide mutations, or various types of genomic rearrangements (e.g., microdeletions, tandem and trinucleotide repeat expansions, microduplication or higher order expansions, aneuploidy). Animal experiments based on inbred rodent strains may provide the most efficient way to explore genetic and epigenetic factors mediating APA and brain development. Comparable to “forward genetics” platforms based on chemical mutagens [77
], rodent-based APA models could provide an age-related mutagenesis experiment that has epidemiological face validity [79
The observation linking APA with risk of schizophrenia has led to the hypothesis that APA-related mechanisms are contributing de novo mutations, which could explain the persistence of schizophrenia in the population in spite of reduced fertility and/or fecundity associated with this disorder [80
]. APA-related mechanisms could accumulate over several generations, with the full clinical phenotype “breaking through” only after a critical threshold of certain mutations have accumulated [81
]. In light of secular trends related to delayed parenthood [83
], and in light of the potential for APA-related mechanisms to accumulate over several generations, the association between APA and subtle deficits in neurocognitive outcomes warrants closer scrutiny. While most of the neurocognitive differences were small at the individual level, these could have important implications from a public health perspective [84