Linking Brain Imaging and Genomics in the Study of Alzheimer's Disease and Aging

Abstract

My colleagues and I have been using positron emission tomography (PET) and magnetic resonance imaging (MRI) to detect and track the brain changes associated with Alzheimer's disease (AD) and normal brain aging in cognitively normal persons with two copies, one copy, and no copies of the apolipoprotein E (APOE) epsilon4 allele, a common AD susceptibility gene. In this review article, I consider how brain imaging techniques could be used to evaluate putative AD prevention therapies in cognitively normal APOE epsilon4 carriers and putative age-modifying therapies in cognitively normal APOE epsilon4 noncarriers, how they could help investigate the individual and aggregate effects of putative AD risk modifiers, and how they could help guide the investigation of a molecular mechanism associated with AD vulnerability and normal neurological aging. I suggest how high-resolution genome-wide genetic and transcriptomic studies could further help in the scientific understanding of AD, aging, and other common and genetically complex phenotypes, such as variation in normal human memory performance, and in the discovery and evaluation of promising treatments for these phenotypes. Finally, I illustrate the push-pull relationship between brain imaging, genomics research, and other neuroscientific research in the study of AD and aging.

Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence

“…These data indicate that reproductive senescence might accelerate the decline in mitochondrial bioenergetics, linking reproductive senescence to the development of a hypometabolic brain phenotype clinically observed in prodromal AD brains [36]. Further, multiple bioenergetic metabolic phenotypes evident at the onset of reproductive senescence indicates the activation of a combination of adaptive responses.…”

Apolipoprotein E Sets the Stage: Response to Injury Triggers Neuropathology

“…Functional brain imaging with fluorodeoxy-glucose ( 18 F), a radiotracer used to study glucose utilization as a surrogate measure of mitochondrial activity, revealed that the cerebral metabolic rate was reduced in both AD patients and in cognitively normal apoE4 carriers in their 20s and 30s, several decades before the typical onset of dementia (Reiman, 2007; Reiman et al, 2004). Gene-expression profiles in postmortem human brain tissue showed a significant association between apoE genotype and the expression levels of multiple mitochondrial respiratory enzymes (Conejero-Goldberg et al, 2011), specifically, a reduction in the expression of electron transport–chain genes in apoE4 carriers (Liang et al, 2008).…”

Characterizing the Role of Brain Derived Neurotrophic Factor Genetic Variation in Alzheimer’s Disease Neurodegeneration

“…Although the causes of late-onset AD pathology are unknown, family studies have demonstrated that complex genetic and environmental mechanisms contribute to disease risk [1,2]. Since the elucidation of the APOE locus in 1993 [3], over 660 candidate genes for AD risk have been identified, however results are inconsistent between studies [4].…”