Unraveling the Role of Mitochondria in Alzheimer’s Disease

Alzheimer’s disease (AD) is an intriguing and still unsolved puzzle that has attracted, over the last decades, the interest of the scientific community. Despite the limited knowledge regarding the initial cause(s) of AD, mitochondrial abnormalities have been pinpointed as one of the earliest and strongest events related with the pathological course of this complex neurodegenerative disease. In this sense, the present chapter addresses three distinct but connected pieces of the AD puzzle: (a) how could defects of mitochondrial bioenergetics and dynamics contribute to AD pathology? (b) Could mitochondrial defects promote the disease-defining amyloid-β‎ and tau pathologies, and vice versa? and (c) Are mitochondria feasible therapeutic targets to postpone AD symptomatology and neuropathology, and, if so, how and when? The understanding and connection of these puzzle pieces provide a more comprehensive picture about the fundamental role of mitochondrial (mal)function in the neurodegenerative processes that occur in AD and propels future research interventions aimed to forestall AD-related pathological phenotype by bolstering mitochondrial “health.”

Hemodynamics in Alzheimer’s Disease and Vascular Cognitive Impairment and Dementia

Hemodynamic impairment is a prominent feature in aging, vascular cognitive impairment and dementia, and Alzheimer’s disease, including patterned changes in cerebral blood flow (CBF) that can be detected prior to concomitant pathologies. These CBF abnormalities drive vascular dysfunction through a variety of biological pathways and ultimately contribute to cerebrovascular disease associated with cognitive impairment. Importantly, the co-existence of cerebrovascular disease and Alzheimer’s disease is exceedingly common and worsens the progression of clinical symptoms, likely through accelerating neurotoxic protein deposition and the loss of cerebrovascular integrity. Emerging evidence further suggests that the brain may be more susceptible to subclinical cardiovascular dysfunction in aging adults, particularly since the accumulation of cardiovascular risk factors over the lifespan creates a more vulnerable vascular system. Although age-associated CBF dysregulation has varied and complex origins, it undoubtedly serves a critical role in the early progression of neurodegenerative disease and may help explain the considerable overlap between the most common clinical dementias.

Structural MRI in Alzheimer’s Disease

Structural magnetic resonance imaging (MRI) is a powerful tool to visualize and quantitate morphological and pathological features of the aging brain. Most work that has used structural MRI to study Alzheimer’s disease (AD) focused on the spatial distribution of atrophic changes associated with disease. These studies consistently show focal atrophy beginning in medial temporal lobes in early and presymptomatic stages of AD before spreading globally throughout the cortical mantle. Normal cognitive aging—aging in the absence of major neurodegenerative disease—on the other hand follows and anterior-to-posterior gradient of atrophic change. In addition to atrophic changes, conventional structural MRI can be used to appreciate markers of small and large vessel cerebrovascular disease, including white matter hyperintensities (WMHs), cerebral microbleeds, and infarction. Studies that have examined cerebrovascular changes associated with AD also show a consistent relationship with risk and severity of clinical AD, particularly with regard to lobar microbleeds and posterior WMH. It is unclear whether cerebrovascular changes play an independent role in the clinical expression of AD or whether it is more mechanistically related, reflecting a core feature of the disease. This chapter reviews recent work on regional atrophy in AD and normal aging, as well as work on small and large cerebrovascular disease in AD.

Apraxic and Action-Intentional Disorders Associated With Vascular and Degenerative Dementing Diseases

“Actions speak louder than words.” Although clinician’s behavioral evaluations of dementia most often include assessing episodic memory, declarative memories (e.g., naming and calculating), and executive functions (working memory, letter–word fluency), one of the most important functions of the brain is programing actions, including “how” to move and “when” to move. Patients with Alzheimer’s disease, vascular dementia, and other forms of dementia often have impairments in the systems that mediate these how-apraxic and when-intentional behaviors. Although the presence of these apraxic and action-intentional disorders may help with diagnosis and help doctors gain a better understand these patients’ disability, these functions are rarely tested and are often not well understood. The goal of this chapter is to describe the signs of the various types of apraxic disorders (limb-kinetic, ideomotor, conceptual, ideational, and dissociation) and well as action-intentional disorders (akinesia-hypokinesia, impersistence, perseveration, and defective response inhibition), how to test for these disorders, and their pathophysiology.

Heterogeneity in Dementia and Mild Cognitive Impairment

Mild cognitive impairment (MCI) and dementia such as Alzheimer’s disease and vascular dementia are heterogeneous conditions that are associated with a chronic course and impairments across a multitude of neurobiological and neuropsychological domains. Until relatively recently, much research has relied on variable-centered techniques (e.g., structural equation modeling, factor analysis, regression) to delineate and study these conditions. This chapter presents evidence of the potential benefits of using person-centered procedures (e.g., latent class analysis) for identifying more homogeneous subgroups of individuals with MCI or dementia that may have distinct correlates, courses, and potential responses to interventions. The research reviewed in this chapter indicates that these strategies permit clinicians and investigators to (a) identify subgroups of individuals who differ in the frequency and/or quality of signs and symptoms, correlates, course, or outcomes, and (b) externally validate and provide support for the predictive validity of these subgroups. Steps for conducting latent class/profile analysis are presented, as well as indices used in selecting the best-fitting model. Implications for assessment, intervention, and future research are provided.

Brain Structural Alterations Common to Cardiovascular Disease Risk Factors and Alzheimer’s Dementia

Over 3,000 publications exist demonstrating that cardiovascular disease risk factors (CVD-RFs) are associated with alterations of brain structure associated with aging and dementia. Using similar neuroimaging techniques, much work has also been done illustrating the specific brain structural changes that are associated with risk for developing dementia, especially Alzheimer’s dementia. This chapter reviews the literature regarding gray matter and subcortical brain structures associated with CVD-RFs and compares it to the literature on gray matter and subcortical brain structural alterations associated with Alzheimer’s dementia. Given the enormous amount of research conducted to date, the authors provide reviews and/or meta-analyses where possible or cite examples, as opposed to providing an exhaustive list of citations when referring to this subject matter. In addition, the authors discuss how such commonalities in brain structural alterations between CVD-RFs and Alzheimer’s dementia may be used to inform brain behavior analyses with a particular focus on the graph theory analytics of tract-based structural connectomics across the spectrum of normal aging to Alzheimer’s dementia.

Heterogeneity in Alzheimer’s/Vascular Spectrum Dementia

Alzheimer’s disease (AD) and vascular dementia (VaD) are considered to be the two most common types of dementia with each of these dementia syndromes believed to represent more or less independent entities. While mixed dementia syndromes are acknowledged, the prevailing point of view continues to suggest that AD and VaD represent disorders with different underlying etiology. This chapter will review some of the recent neuropathological and neuropsychological literature suggesting considerable heterogeneity between AD and VaD. It is our contention that the literature reviewed in this chapter supports the notion that neuropsychological syndromes seen in AD/VaD dementia, in addition to their underlying biological substrate, are best understood as existing along a clinical/pathological continuum or spectrum. This heterogeneity should be leveraged to construct a more sophisticated and heuristically meaningful way to classify patients with dementia.

Vascular Risk Factors and Their Relationship to Brain Aging

The Framingham Heart Study (FHS) was established in 1948 and is the longest, ongoing prospective cohort study studying cardiovascular diseases and stroke. Initially, the FHS was primarily focused on cardiovascular diseases; however, over recent decades data from the FHS have found that lifetime exposure to major cardiovascular risk factors such as hypertension, diabetes mellitus, arterial stiffness, and pressure pulsatility adversely impact neuropsychological functioning particularly in older individuals contributing to the onset of dementia including Alzheimer’s disease. Research from the FHS suggest that appropriate management of cardiovascular risk factors as well as healthy lifestyle practices that include regular blood pressure monitoring, not smoking, and eating a choline-rich diet appear to minimize neuropsychological decline as well as dementia onset.

Arterial Stiffening and Cerebrovascular Resistance in Cognitive Decline and Alzheimer’s Disease

The impact of vascular factors on cognitive decline and Alzheimer’s disease (AD) has been increasingly recognized. AD and vascular cognitive impairment exhibit significant overlap, individuals with vascular risk factors experience elevated risk for AD, and vascular mechanisms have been implicated in the genetic and pathological processes underlying development of AD. Arterial stiffening and cerebrovascular resistance have been identified as potential junctions through which vascular dysfunction promotes AD pathogenesis and cognitive decline. This chapter outlines the pathophysiology of arterial stiffening and cerebrovascular resistance, beginning in the aorta and small vessels of the brain, respectively. As these processes proliferate, cerebral circulation is disrupted, compromising capacity to meet neuronal metabolic needs and culminating in cognitive declines. An overview is provided of in vivo markers for arterial stiffening and cerebrovascular resistance, including methods employing pulse wave velocity, transcranial Doppler ultrasonography, and arterial spin labeling magnetic resonance imaging. Relevant research developments and their implications for conceptualization of vascular contributions to cognitive decline are discussed.

The Blood–Brain Barrier in Cognitive Decline and Alzheimer’s Disease

The neurovascular unit is a multicellular organ that has attracted recent attention as a key microvascular regulator of cerebral blood flow and blood–brain barrier permeability that is implicated in homeostatic and pathological processes impacting cognitive function. Breakdown of the blood–brain barrier invariably causes brain tissue damage and dysfunction due to influx of toxic blood proteins, cells, ions and metals. Clinical studies employing markers of blood–brain barrier permeability suggest an important role in vascular and neurodegenerative dementias. The chapter discusses how the introduction of new neuroimaging and biomarker technologies has opened new pathways of investigation into the blood–brain function in Alzheimer’s disease.