Multiple combinations of co-factors produce variants of age-related cognitive decline: A theory

Canadian Journal of Experimental Psychology, Sep 2002 by Robert J McDonald

Abstract A theory concerning the etiology of agerelated cognitive decline, like Alzheimer's disease (AD), is presented. The view utilizes the idea that this form of dementia is a etiologically complex and heterogeneous brain disorder that is caused by various co-factors. A particular patient with AD would have some combination of these co-factors present but the exact type and combinations might be different from another patient. This theory could also be used to explain other forms of dementia and age-related cognitive decline and the differences in severity of memory impairments associated with each. The co-factors in the present model include genes, neurotransmitter changes, vascular abnormalities, stress hormones, circadian rhythms, head trauma, and seizures.

"...how could I ever forget them..." Charles M. Schulz, 2000

The debate concerning the relationship between normal aging and dementia continues in the literature. The continuity model (Huppert, 1994), as it is sometimes referred, suggests that the variables associated with dementia fall along a continuum with normal aging. For example, Alzheimer's disease (AD) would simply differ in the degree of changes to the brain and neural function, but not in the kind of changes found. These variables have traditionally included brain pathology, neurochemical changes, and cognitive function. This view suggests that a deep understanding of the relationship between normal aging and dementia will provide critical information about cognitive decline in the general population, as well as the devastation experienced by Alzheimer's patients and those close to them. Others suggest that dementia is a set of diseases quite distinct from normal aging. One possibility that will be explored in this paper is that within, and across, current categories of dementia, the etiology of individual cases might be based on different combinations of cofactors that interact synergistically on a common initial neural target.

Dementia is defined as cognitive impairments that are serious enough to disrupt normal daily living. The dementias include over 50 different disorders, including vascular dementia, human Prion diseases, Parkinson's disease, Pick's disease, frontal disorders, dementia with Lewy bodies, Huntington's disease, Alzheimer's disease, and others (Haase, 1977). Alzheimer's disease is the most common cause of dementia accounting for over 65% of all forms of dementia, if combined with vascular pathology. The prevalence of the disease in the general population is correlated with chronological age, with rare reports in the fourth decade and then logarithmic increases over subsequent decades (Katzman & Kawas, 1994).

Although the term dementia encompasses a large number of disorders, this paper will focus on Alzheimer's disease. Alzheimer's disease will be used as an exemplar of a disorder that has initial pathological effects on the hippocampal formation as its core target (Ball, Fisman, Hachinski, Blume, Fox, Kral, Kirshen, Fox, & Merskey, 1985). After providing details about co-factors implicated in Alzheimer's disease and setting up the general model, examples of the possible etiologies of age-related cognitive decline will be presented.

The onset of Alzheimer's disease is often first detected by the patients themselves or family members and is usually manifested by changes in personality (Reisberg, 1983). Following these subtle changes, anterograde memory impairments without any obvious sensory, motor, or motivational deficits are the defining feature of the early stages of this disorder (Arnold et al., 1994; Hyman et al., 1984; Van Hoesen, Hyman, & Damasio, 1991). These memory deficits are usually seen on neuropsychological tests that are sensitive to medial temporal lobe damage (Grady et al., 1988; Growdon, 1995). The medial temporal lobe includes various structures implicated in mammalian learning and memory processes, including the hippocampus, amygdala, and parahippocampal cortex. The hippocampus is a learning and memory system that is critical for the acquisition, encoding, and retrieval of representations of the various elements that define a specific event and the context in which it occurred (Hirsh, 1974; O'Keefe & Nadel, 1978; Sutherland & Rudy, 1989). The hippocampus in humans has been described as an episodic memory system essential for conscious awareness of personal experiences (Schacter & Tulving, 1994; Scoville & Milner, 1957; Moscovitch, 1995). The amygdala has been implicated in tracking the biological significance of stimuli in the environment (Cador, Robbins, & Everitt, 1989; Hiroi & White, 1991; Kapp, Frysinger, Gallagher, & Haselton, 1979). A significant portion of the parahippocampal cortex called the perirhinal cortex has been implicated in object memory (Mumby & Pinel, 1994). There is evidence to suggest that the brain damage and pathology associated with AD begins in the parahippocampal cortex and then spreads to the hippocampus and amygdala (Van Hoesen et al., 1991), and these changes correlate strongly with the specific memory impairments found in the early and mid-stages of AD. The transition between specific medial temporal lobe memory deficits to more global deficits correlates with the location and extent of brain degeneration.