Background There has been a long argument over whether or not schizophrenia is a neurodegenerative disorder associated with progressive brain changes and increasing cognitive impairment. Building on the fact that schizophrenia is highly heritable and overlaps genetically with general cognitive ability, we investigated whether common genetic variants associated with schizophrenia additively confer a stable deficit in cognitive ability, a greater risk of cognitive decline over time, or both, over the 8-year follow-up, independently from the effects of the apolipoprotein E gene (APOE-ε4), in phenotypically well-defined sample of healthy older adults.

Methods We used data from the English Longitudinal Study of Ageing study which encompassed 6817 population-representative English adults who were followed-up for 8 years. Cognitive function was measured with well-established tests of memory (tests of immediate and delayed word recall combined into a single measure of correctly recalled words) and executive function (a test of verbal fluency where participants name as many animals as possible in a minute). Polygenic score for schizophrenia (SZ-PGS) was calculated based on the results from Psychiatric Genomics Consortium. Linear mixed effect models with maximum likelihood estimation were used to estimate baseline status and rate of change in cognition associated with SZ-PGS.

Results The sample baseline mean age was 64.3 years old (standard deviation (SD)=9.3, range=50–101); 25.3% (N=1724) of participants were carriers of APOE-ε4 and 46.2% (N=3159) were men. The average baseline memory score was 10.4 (SD=3.4) and executive function score was 20.7 (SD=6.3). One standard deviation increase in SZ-PGS was associated with a lower baseline executive function score (-0.23, 95%CI-0.38 – -0.08) but not memory. SZ-PGS was not associated with rates of change in these cognitive domains during the 8-year follow-up period. However, APOE-ε4, tobacco smoking and lower wealth were associated with a decrease in the rate of memory and executive function during follow-up.

Discussion Common genetic variants associated with schizophrenia additively confer a stable deficit in cognitive ability but not cognitive ageing. The fact that we observed cognitive decline in our sample over the 8-year follow-up, associated with of APOE-ε4, tobacco smoking and lower wealth demonstrates that our study had the capacity to show cognitive decline. Therefore, we may conclude that while genetic susceptibility to schizophrenia conveys developmental cognitive deficit, it does not result in an ongoing cognitive decline, at least in later life. This, in turn, disproves the Kraepelinan notion of schizophrenia as a genetically determined progressively deteriorating brain disease.