Medical Research: What is the background for this study? What are the main findings?
Dr. Ramanan: Impairment in episodic memory is one of the first clinical deficits in early Alzheimer’s disease, the most common cause of dementia. Among other examples, this might be reflected as an inability to recall an article recently read or as difficulty remembering what one had for dinner last night. Unfortunately, the genetic and environmental mechanisms underlying these deficits are not fully understood. Our goal was to discover new genes and pathways underlying memory performance to help identify potential drug targets for protecting against and ultimately reversing memory loss in dementia and normal aging.
Through studying a large representative sample of older Americans, we discovered a variant (single nucleotide polymorphism or SNP) in the FASTKD2 gene associated with better memory performance and replicated this finding in independent samples. We then integrated additional data to extend our understanding of the effect of this SNP. For example, we know that the hippocampus is a vital brain structure for encoding and retrieving memories and it is well-understood that decreased hippocampal volume is a key early marker of Alzheimer’s disease and one that can be measured noninvasively through magnetic resonance imaging (MRI). We predicted that this new memory-protective SNP would be associated with increased hippocampal volume and this turned out to be true. We also discovered that carriers of this memory-protective SNP exhibited lower levels of proteins involved in cell death in the cerebrospinal fluid bathing the brain and spinal cord, a striking finding given that FASTKD2 encodes a protein that appears to promote apoptosis (i.e., programmed cell death). Together, these convergent findings are consistent with a neuroprotective effect of this novel SNP discovery. More broadly, our results nominate FASTKD2 and its functional pathways as potential targets for modulating neurodegeneration to combat memory loss in older adults.
Medical Research: What should clinicians and patients take away from your report?
Dr. Ramanan: To our knowledge this represents the largest genetic study of human memory to date and includes more than 14,000 older adults from 6 independent cohorts centered at numerous institutions across North America and Europe. The greatest value of this study is in how it enhances our understanding of the genetic mechanisms driving memory functioning. Particularly given that our top discovery was protective, we will be interested to follow whether drug targeting of this gene and pathway may be used to protect against or reverse neuronal dysfunction and memory loss. Given the rising incidence and burdens of dementia, discovering more of the factors underlying what is frequently described as the “Alzheimer’s epidemic” will be crucial for predicting risk and developing effective treatments.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Ramanan: Functional genomics experiments using animal and cultured cell model systems will be valuable for directly testing the impact of drugs targeting FASTKD2 and its functional pathways. We would also like to study additional large datasets not analyzed in this report, particularly to assess other genes showing some signal in our analysis, such as MTOR which is a major active drug target for Alzheimer’s due its known roles in amyloid and tau pathology. Research using next generation sequencing data, which provides much more detailed views of DNA and RNA, will also help to characterize the mechanism of action for the SNPs nominated in this study and may identify other nearby variants which were too rare to identify in our analyses.
FASTKD2 is associated with memory and hippocampal structure in older adults
V K Ramanan, K Nho, L Shen, S L Risacher, S Kim, B C McDonald, M R Farlow, T M Foroud, S Gao, H Soininen, I Kłoszewska, P Mecocci, M Tsolaki, B Vellas, S Lovestone, P S Aisen, R C Petersen, C R Jack, L M Shaw, J Q Trojanowski, M W Weiner, R C Green, A W Toga, P L De Jager, L Yu, D A Bennett, A J Saykin and for the Alzheimers Disease Neuroimaging Initiative (ADNI)27
Molecular Psychiatry , (11 November 2014) | doi:10.1038/mp.2014.142