Do synaptic changes occur before old age in people at high genetic risk of Alzheimer's disease?

• Published in: The Lancet (British edition) Vol. 387; p. S92
• Main Authors: Sinclair, Lindsey, Dr, Love, Seth, Prof
• Format: Journal Article
• Language: English
• Published: London Elsevier Ltd 25-02-2016; Elsevier Limited
• Subjects: Alzheimer's disease; Dementia disorders; Genotypes; Internal Medicine; Risk factors
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(16)00479-7

Abstract Background Possession of an ɛ4 allele of the APOE gene is the main known genetic risk factor for late-onset Alzheimer's disease. Neuropathological changes of Alzheimer's disease can be found much earlier and are more pronounced in people with an ɛ4 allele than in those without this allele. When or how these changes begin are not known. We tested our hypothesis that ɛ4 allele possession in adults aged under 75 years is associated with alterations in concentrations of synaptic proteins. Methods We obtained samples from UK brain banks of superior temporal gyrus and hippocampus from 103 individuals aged 75 years or younger with no evidence of dementia. The proteins synaptophysin, PSD-95, drebrin, septin-7, and SNAP-25 were measured by ELISA and corresponding gene expression— SYP, DLG4, DBN1, SEPT7 , and SNAP-25 with RT-PCR. APOE genotyping was performed by liquid phase two single nucleotide polymorphism genotyping. We corrected for neuronal content by ELISA measurement of neuron-specific enolase. Regression models controlled for important confounders. Findings There were five genotypes (one e22, 15 e32, 57 e33, 22 e34, five e44). The ɛ33 group was the reference group in all regressions. There was a significant increase in gene expression of SNAP-25 (difference between geometric means 0·2, p=0·038) and SYP (0·3, p=0·018) in the superior temporal gyrus in ɛ4 carriers but only a non-significant trend in the protein concentrations. Drebrin protein was increased in the hippocampi of the ɛ32 group (difference between means 3·4 ng/μL, p=0·019). There was a non-significant trend towards PSD-95 being increased in the hippocampus in the ɛ32 group (difference between means 0·6 ng/μL, p=0·079). Since each protein measure is a crude proxy measure of post-synaptic density and has measurement error, a summary z-score was also used. The summary score supported a per genotype difference in post-synaptic density in the hippocampus (difference from reference group 2·3, p=0·02). Expression of these genes was not increased in the ɛ32 group, but PSD-95 expression was increased in ɛ4 carriers (difference between geometric means 0·3, p=0·017) despite no protein differences. Interpretation Our finding that the ɛ32 group had an increase in post-synaptic proteins despite a lower risk of Alzheimer's disease than the other groups is intriguing. Low numbers in our study prevent a definitive conclusion, despite our procurement of tissue from multiple UK brain banks. Funding Wellcome Trust Research Training Fellowship.