Strengths and limitations

To our knowledge, this study is the first to use an individual participant meta-analysis methodology to examine the association between socioeconomic variables and dementia. In contrast to previous literature-based analyses, an individual participant meta-analysis has the advantage of providing precise estimates of risk marker-disease relationships, reliable information on the shape of a given risk factor-disease relationship (for example dose-response v. threshold) and a consistent approach to statistical control for plausible covariates and subgroup analyses. We used a large, well-characterised sample that is representative of the general population in England. This provided sufficient power to allow gender-specific analyses and allowed us to explore the role of a series of explanatory factors. By including two measures of socioeconomic status at different time points we offer some insights into the influence of life-course socioeconomic status on dementia risk.

This notwithstanding, the data have their limitations. Despite the large sample and over 12 000 deaths during follow-up, there were only 622 dementia-related deaths. This is due to the wide age range of individuals included in the survey at baseline - adults aged 35 and over. Although this wide age range increases the generalisability of the findings, it has resulted in a relatively small proportion of individuals dying with dementia and consequently wide confidence intervals, limiting the conclusions that can be drawn. The identified gender differentials should be viewed in the light of this question of power. The number of dementia-related deaths in this study is likely to have been additionally affected by the unavoidable problems of underdiagnosis of dementia in the community, ^{Reference Sampson, Blanchard, Jones, Tookman and King23} underrecording of dementia on death certificates ^{Reference Martyn and Pippard24} and diagnoses being inaccurately coded. Non-recording of dementia on death certificates has been highlighted as an important issue, but this seems to be improving. A recent study identified that 71.5% of a clinic sample diagnosed with probable Alzheimer's disease had dementia correctly recorded on their death certificate. ^{Reference Russ, Batty and Starr25} There was no association in that sample between correct dementia certification and area deprivation or premorbid IQ estimated by the National Adult Reading Test (unpublished results available from the author on request), suggesting that individuals reported as having dementia on their death certificate are representative of the population of people with diagnosed dementia in the community, at least in terms of intelligence and level of deprivation.

Comparison with previous studies

Dementia was estimated to affect over 24 million people globally in 2001 and this is expected to rise to over 80 million by 2040. ^{Reference Ferri, Prince, Brayne, Brodaty, Fratiglioni and Ganguli26} In England and Wales the prevalence of dementia is estimated to vary from approximately 1.5% at age 65-69 to approximately 25.3% over the age of 84. ^{Reference MRC27} Dementia incidence ranges from 7.4 (95% CI 3.6-16.1) per 1000 person-years at age 65-69 to 84.9 (95% CI 63.0-107.8) per 1000 person-years over the age of 84. ^{Reference Matthews and Brayne28} However, existing prospective studies of socioeconomic factors have generally been small in scale - only one analysis reported a combined sample larger than 10 000 ^{Reference Launer, Andersen, Dewey, Letenneur, Ott and Amaducci19} - and few studies measure socioeconomic status at more than one time point. ^{Reference Persson and Skoog8} On a related note, the association between education and dementia risk has been reported to be present in women but not in men; ^{Reference Launer, Andersen, Dewey, Letenneur, Ott and Amaducci19} it is therefore important that studies are sufficiently large to allow gender-specific analyses. In addition, for older participants - who are most likely to have died with dementia during follow-up - the social class may have been allocated to females on the basis of their husband's occupation, further muddying the waters.

Factors across the lifespan have been implicated in the aetiology of dementia. A series of studies confirm a link between early life socioeconomic status and dementia risk with early parental death - and, potentially, consequent socioeconomic hardship - being highlighted as an important risk factor. ^{Reference Norton, Ostbye, Smith, Munger and Tschanz29}

A total of 51 of 88 studies included in a systematic review ^{Reference Sharp and Gatz6} reported a significant association between a basic education and dementia risk, the remainder reporting no effect. However, only two previous studies report gender-specific effects, showing an effect of education on dementia risk in women but not in men, as found in the current study.

In England, the Education Act 1918 raised the school leaving age from 12 to 14. It was further increased to 15 in 1947 and to 16 in 1973. Participants in the Health Survey for England came from all these educational eras and overall approximately half of men and women stayed on after completion of the compulsory period of education. However, individuals were much more likely to remain in education longer if they were born later: 86.7% of women and 87.2% of men born after 1956 (who therefore had to remain in school until 16) compared with 17.8% of women and 18.5% of men born before 1906 and who could therefore leave school at 12. However, the reference category used, of individuals who remained in full-time education up to 16 years or later, exactly matches those who remained in education after the compulsory school leaving age.

Since children scoring higher on IQ tests, as well as children from a higher occupational social class, are more likely to be given the opportunity to remain in education for longer, a number of studies have investigated the association between childhood mental ability and dementia. A Scottish study identified 50 participants in the 1932 Scottish Mental Survey who had developed dementia and ascertained that their scores on the Moray House Test in 1932 had been significantly lower than their peers in the same area who did not develop dementia. ^{Reference Whalley, Starr, Athawes, Hunter, Pattie and Deary30} However, a larger subsequent study confirmed that this was the case for vascular dementia but not for Alzheimer's disease. ^{Reference McGurn, Deary and Starr31} On the other hand, the Nun study identified that low linguistic ability at a mean age of 22 was associated with Alzheimer's disease in the 14 study participants aged 79-96 whose brains were neuropathologically examined post-mortem. ^{Reference Snowdon, Kemper, Mortimer, Greiner, Wekstein and Markesbery32}

Occupation in adulthood has also been shown to be associated with dementia risk - high ‘occupational attainment’ is associated with lower dementia risk. ^{Reference Stern, Gurland, Tatemichi, Tang, Wilder and Mayeux33} However, since the pathology of Alzheimer's disease and probably vascular dementia develops over a very long period of time ^{Reference Braak and Braak34} risk factors must be measured sufficiently early in life for them to have an effect, and exposures immediately before retirement may have little or no effect on dementia risk.

Few studies measure socioeconomic status across the whole lifespan. One study to do so identified early parental death, manual work and physical illness in the spouse or serious illness in a child, both after the age of 65, to be independent risk factors for dementia. ^{Reference Persson and Skoog8} However, many of the socioeconomic factors measured in studies are closely linked and disentangling their individual effects can be extremely difficult.

Mechanisms of effect

The role of education and mental ability as potential risk factors for dementia has been linked to the hypothesis of cognitive reserve - that certain individuals' brains are structurally or functionally more resilient to disease or injury. This sprang from the observation that there was no clear relationship between the extent of brain pathology and the clinical manifestations of dementia in an individual. Cognitive reserve might relate to a person's intrinsic make up or could result from external experience, i.e. education and occupation. Indeed, there is evidence that occupation is associated with differences in parietal blood flow in Alzheimer's disease that could be a marker of reserve. ^{Reference Stern, Alexander, Prohovnik, Stricks, Link and Lennon35}

Criticisms of the cognitive reserve hypothesis include the suggestion that the effect merely reflects performance on cognitive tests ^{Reference Gilleard36} or that the effect is mediated by lifestyle factors and cerebrovascular risk. ^{Reference Del Ser, Hachinski, Merskey and Munoz37} The present study used clinical diagnoses of dementia recorded on death certificates and two measures of socioeconomic status at different stages of life. This allows us to demonstrate that the observed association between education and dementia in women was not mediated by adult occupation.

Since an individual with more cognitive reserve would have more advanced pathological changes at the time of diagnosis, it has been suggested that this could be linked with a swifter decline and poorer survival. Some studies have found that individuals with Alzheimer's disease and higher educational and occupational attainment declined faster in their performance on cognitive tests. ^{Reference Stern, Albert, Tang and Tsai38} This aspect of the cognitive reserve hypothesis was not examined by the current study.

Implications

An association between lower educational attainment and dementia in women but not men has a number of implications. First, the mechanism of this association, currently hypothesised to relate to cognitive reserve, must be clarified. Second, the reason that the association is observed only in women should be investigated. It may be that fewer women entered further education and that those who did had to be very intelligent to do so. Thus, length of education in these cohorts could be confounded by intelligence in women to a greater extent than men. However, the identified gender difference may also potentially hold the clue to an intervention to decrease the risk of dementia in women, if a modifiable risk (or protective) factor could be identified. Lastly, if this association were to reflect a causative link between education and dementia risk, promoting higher and further education, especially for women, could have important public health consequences for a common and serious condition.

In conclusion, this large prospective study shows an association between leaving full-time education at a younger age and dementia death in women, but not in men. This relationship remained after adjustment for alcohol, smoking, cardiovascular disease, diabetes, psychological distress and occupational social class. An association between lower occupational social class and dementia death that did not reach statistical significance at conventional levels was also observed in men, but not in women.