Drugs developed to slow, halt or reverse the progression of Alzheimer’s Disease (AD) have failed to alter the course of the disease in clinical trials. One possible explanation is that drugs need to be administered earlier, before the onset of clinical symptoms. AD-related pathological processes that occur before clinical symptoms emerge define the preclinical phase of the disease. Neuroimaging biomarkers and genetics together present a powerful system for characterizing potential preclinical changes in the brain. The work presented in this volume is predicated on the need for a better understanding of genetic risk and neuroimaging biomarkers for AD in healthy adults. In Chapter 1, a thorough review of neuroimaging genetics in AD is presented. The studies described in Chapters 2 and 3 explore the relationship between functional connectivity and the apolioprotein E (APOE) risk allele, APOEε4. In the first study a pattern of context-dependent connectivity was uncovered that indicates APOEε4 carriers disengage key cortical regions from the hippocampus during a memory task. These findings support the growing consensus that functional connectivity changes may be among the earliest preclinical markers of AD-related changes in the brain. The second study utilized resting state fMRI scans from 570 healthy college-age adults. Young carriers of APOEε4 showed decreased connectivity between key regions involved in AD and increased segregation of task-positive and task-negative regions. This work is a crucial reminder that genetic risk for AD has important implications across the lifespan and that gene-biomarker associations must be tracked over time to identify changes that might be signs of imminent clinical decline. In Chapter 4, the focus expands to include additional genetic risk factors for AD beyond APOE. This study is the first to show that a genetic risk score for AD is significantly associated with hippocampal thinning over two years in a cohort of older, cognitively healthy adults. Finally, Chapter 5 is a call for the further development of polygenic approaches to studying neuroimaging markers of genetic risk for AD. Together, this volume represents steps toward understanding how genetic risk for AD and neuroimaging can be used to identify individuals at greatest risk for decline.

Whole-brain structural and functional connectivity networks can be assessed using diffusion-weighted MRI (DW-MRI) and functional MRI (fMRI), respectively. When the brain is parcellated into its constituent subregions, specific methods quantify the relative connectivity strengths between pairs of regions. The calculation of connectivity between all pairs of regions produces a connectivity matrix. With such a matrix, mathematical methods from graph theory characterize the network for global properties of integration, segregation, and robustness. At the regional level, these methods quantify specific properties such as connection density, convergence, and isolation. In this work, we apply these methods to understand how the possession of the Apolipoprotein E ε4 allele, the primary genetic risk factor for late-onset Alzheimer's Disease (AD), contributes to global and local alterations of structural and functional connectivity. In Chapter 2, we find that DW-MRI-based fiber tractography networks in aging APOE-4 carriers exhibit accelerated negative correlations between age and clustering coefficient, a measure of local axonal connection density. This trend occurs simultaneously with reductions in global cortical thickness and decrease performance on episodic memory tests. In a highly similar population, we examined fMRI-based functional connectivity networks during performance on an episodic memory task (Chapter 3). APOE-4 carriers demonstrated reduced activation during memory encoding in the entorhinal cortex, a locus of early disease change in Alzheimer's disease. The degree of activation in this region correlated with the amount of functional brain integration, suggesting a global basis for local alterations in neuronal activity. In Chapter 4, we assessed hippocampal functional and structural connectivity during episodic memory consolidation in healthy young adults. Results indicate that elevated functional connectivity in a hippocampal-cortical network was important for the process of consolidation. The structural connections of this network all traversed the parahippocamal gyrus, an area of known structural atrophy in individuals at genetic risk for AD. In Chapter 5 we describe a web-based tool for the public sharing and analysis of brain connectivity matrices, and then apply it to reveal substantial differences in the topology of whole brain structural and functional networks. Finally, Chapter 6 contains a model of cortico-hippocampal connectivity that unifies the findings from these studies.

Diseases of aging, such as Alzheimer’s, occur at the hands of many cumulative risk factors occurring over a lifetime. As with virtually all non-mendelian diseases, genetics and environment play essential and synergistic roles in disease development. Disentangling the relative contributions of risk factors will aide future prevention in youth to reduce an individual’s risk later in life. The same risk factors may also serve as biomarkers signaling brain changes in advance of disease state. Once we have successful treatments, early identification and intervention will be the best, and perhaps only way to prevent Alzheimer’s disease.

The goal of this research is to identify early cognitive and physiological changes or differences in subjects at high-risk for AD, as well as to identify pathological features that are most related to memory decline. This knowledge has strong implications for identification of both Alzheimer’s disease and the optimal targets for treatment.

In chapter 1 we use the positron emission tomography (PET) ligand [18F]FDDNP, a marker for beta-amyloid plaque and tau neurofibrillary tangle deposition, to investigate the relationship between lifestyle factors, protein deposition and severity of memory impairment. We show that BMI and age are significant predictors of plaque and tangle deposition that correlates with memory impairment and Alzheimer’s disease.

In chapter 2, we combine structural magnetic resonance imaging (MRI), cortical segmentation and the PET ligand [18F]MPPF, which selectively binds the serotonin (5-HT) 1A receptor. We quantify hippocampal 5-HT1A receptor densities in older adults because the hippocampus is integral to the formation of new memories and one of the earliest brain regions to show AD-related changes. Receptor density is a proxy for neuronal loss, and can be compared to measures of hippocampal volume obtained with cortical segmentation. We find that 5-HT1A receptor density predicts differences in memory performance across all subjects, and is highly correlated in subjects with below-average memory performance. We also see lateralization of binding density consistent with previously suggested functional differences.

In chapter 3 we investigate the relationship between anxiety and memory loss with the 5HT1A receptor, known to influence anxiety behavior, in regions previously shown to play a role in anxiety disorders such as the amygdala, insula and cingulate cortex. Though, surprisingly, we do not see a relationship between 5-HT1A receptor density and anxiety in amygdala, we do see a significant relationship between receptor density and anxiety in insula, and this relationship is also related to working memory deficits and a perceived increase in forgetfulness. Furthermore this relationship is in direct opposition in women and men. While women show a decrease in 5-HT1A receptor density with increased anxiety, men show the inverse. This supports previous suggestion of significant sex differences in the serotonin system, and a relationship between mood disorders such as anxiety and depression and risk of later cognitive decline.

Decades of accumulated scientific evidence has demonstrated that vital factors (e.g., amyloid-β (Aβ) and the gene apolipoprotein E (APOE) ε4) contribute to the neuropathological changes and memory deficits observed in Alzheimer's disease (AD) and related dementias. Identifying these factors prior to disease onset could facilitate earlier access to disease-modifying treatments or promote healthy lifestyle modifications that might reduce neuropathology or cognitive deficits. However, the relationship between plasma-derived Aβ, APOE ε4, and brain atrophy in older adults before the manifestation of clinically relevant memory loss remains unclear. Furthermore, brain stimulation has emerged as a powerful approach for developing novel neuromodulatory therapies for those with deficits in cognition. Thus, these techniques may be used as potential treatments for those at risk for AD and other severe memory impairments.

The studies from this dissertation investigated the neural correlates and causal outcomes of cognitive and memory-related systems in the aging human brain. The first study examined the relationship between plasma-derived Aβ, APOE ε4, and brain atrophy in a large sample of 160 healthy older adults (ages 50+). The second and third studies showed promising effects on memory using invasive and non-invasive brain stimulation in cognitively healthy adults without memory impairments. Together these findings suggest that genetic, biological, and neural determinants could be combined with neuroimaging-guided brain stimulation to better identify individuals at risk for AD and improve their hippocampal-related memory.

Future studies of brain aging in healthy and memory-impaired older adults should monitor the molecular and neurobiological markers indicative of cognitive function and study novel methods like brain stimulation therapies. Since cognition is detrimentally influenced by these factors ensuring memory-enhancing therapies are effective despite indicators of impairment is necessary for the development of clinically viable treatments of benign senescence or more advanced impairment. Using different MRI modalities, the structural and microstructural properties of the brain can be used to predict treatment response or optimize hippocampal network targeting to restore aberrant function and alleviate the deficits associated with progressive memory loss.

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