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Schizophrenia polygenic risk predicts general cognitive deficit but not cognitive decline in healthy older adults.

ABSTRACT: There has been a long argument over whether schizophrenia is a neurodegenerative disorder associated with progressive cognitive impairment. Given high heritability of schizophrenia, ascertaning if genetic susceptibility to schizophrenia is also associated with cognitive decline in healthy people would support the view that schizophrenia leads to an accelerated cognitive decline. Using the population representative sample of 6817 adults aged >50 years from the English Longitudinal Study of Ageing, we investigated associations between the biennial rate of decline in cognitive ability and the schizophrenia polygenic score (SZ-PGS) during the 10-year follow-up period. SZ-PGS was calculated based on summary statistics from the Schizophrenia Working Group of the Psychiatric Genomics Consortium. Cognition was measured sequentially across four time points using verbal memory and semantic fluency tests. The average baseline verbal memory was 10.4 (SD?=?3.4) and semantic fluency was 20.7 (SD?=?6.3). One standard deviation (1-SD) increase in SZ-PGS was associated with lower baseline semantic fluency (??=?-0.25, 95%CI?=?-0.40 to -0.10, p?=?0.002); this association was significant in men (??=?-0.36, 95%CI?=?-0.59 to -0.12, p?=?0.003) and in those who were aged 60-69 years old (??=?-0.32, 95%CI?=?-0.58 to -0.05, p?=?0.019). Similarly, 1-SD increase in SZ-PGS was associated with lower verbal memory score at baseline in men only (??=?-0.12, 95%CI?=?-0.23 to -0.01, p?=?0.040). However, SZ-PGS was not associated with a greater rate of decline in these cognitive domains during the 10-year follow-up. Our findings highlight that while genetic susceptibility to schizophrenia conveys developmental cognitive deficit, it is not associated with an ongoing cognitive decline, at least in later life. These results do not support the neo-Kraepelinian notion of schizophrenia as a genetically determined progressively deteriorating brain disease.

SUBMITTER: Kepinska AP

PROVIDER: S-EPMC7722936 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Schizophrenia polygenic risk predicts general cognitive deficit but not cognitive decline in healthy older adults.

Kępińska Adrianna P AP MacCabe James H JH Cadar Dorina D Steptoe Andrew A Murray Robin M RM Ajnakina Olesya O

Translational psychiatry 20201208 1

There has been a long argument over whether schizophrenia is a neurodegenerative disorder associated with progressive cognitive impairment. Given high heritability of schizophrenia, ascertaning if genetic susceptibility to schizophrenia is also associated with cognitive decline in healthy people would support the view that schizophrenia leads to an accelerated cognitive decline. Using the population representative sample of 6817 adults aged >50 years from the English Longitudinal Study of Ageing ...[more]

PMID: 33293510

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Project description:BackgroundHere, we address a pivotal factor in Alzheimer's prevention-identifying those at risk early, when dementia can still be avoided. Recent research highlights an accelerated forgetting phenotype as a risk factor for Alzheimer's disease. We hypothesized that delayed recall over 4 weeks would predict cognitive decline over 1 year better than 30-min delayed recall, the current gold standard for detecting episodic memory problems which could be an early clinical manifestation of incipient Alzheimer's disease. We also expected hippocampal subfield volumes to improve predictive accuracy.MethodsForty-six cognitively healthy older people (mean age 70.7 ± 7.97, 21/46 female), recruited from databases such as Join Dementia Research, or a local database of volunteers, performed 3 memory tasks on which delayed recall was tested after 30 min and 4 weeks, as well as Addenbrooke's Cognitive Examination III (ACE-III) and CANTAB Paired Associates Learning. Medial temporal lobe subregion volumes were automatically measured using high-resolution 3T MRI. The ACE-III was repeated after 12 months to assess the change in cognitive ability. We used univariate linear regressions and ROC curves to assess the ability of tests of delayed recall to predict cognitive decline on ACE-III over the 12 months.ResultsFifteen of the 46 participants declined over the year (≥ 3 points lost on ACE-III). Four-week verbal memory predicted cognitive decline in healthy older people better than clinical gold standard memory tests and hippocampal MRI. The best single-test predictor of cognitive decline was the 4-week delayed recall on the world list (R2 = .123, p = .018, β = .418). Combined with hippocampal subfield volumetry, 4-week verbal recall identifies those at risk of cognitive decline with 93% sensitivity and 86% specificity (AUC = .918, p < .0001).ConclusionsWe show that a test of accelerated long-term forgetting over 4 weeks can predict cognitive decline in healthy older people where traditional tests of delayed recall cannot. Accelerated long-term forgetting is a sensitive, easy-to-test predictor of cognitive decline in healthy older people. Used alone or with hippocampal MRI, accelerated forgetting probes functionally relevant Alzheimer's-related change. Accelerated forgetting will identify early-stage impairment, helping to target more invasive and expensive molecular biomarker testing.

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Schizophrenia polygenic risk predicts general cognitive deficit but not cognitive decline in healthy older adults.

Publications

Schizophrenia polygenic risk predicts general cognitive deficit but not cognitive decline in healthy older adults.

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