Open peer commentaryCognitive and behavioral heterogeneity in Alzheimer’s disease: seeking the neurobiological basis
Introduction
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the central nervous system (CNS) affecting primarily limbic, paralimbic, and neocortical structures. At the molecular level, the primary abnormalities include abnormal processing of amyloid precursor protein (APP), hyperphosphorylation of tau protein, and apoptotic-like cell death [1]. Neuronal death in specific transmitter source nuclei results in deficiencies of acetylcholine, serotonin, and norepinephrine that contribute to the matrix of pathological changes underlying the clinical syndrome [2]. Alzheimer’s type pathology is promoted by the presence of the apolipoprotein E4 allele [3] and accompanied by a neuroimmune response [4]. The tempo of these changes and their regional distribution results in a recognizable clinical syndrome that has high predictive value for the pathological diagnosis of AD [5].
Despite the presence of core clinical features that facilitate accurate clinical recognition, there is substantial clinical heterogeneity among patients with AD. There are variations in both the cognitive and the behavioral manifestations of the disorder. Currently there is limited insight into the neurobiological basis of this clinical heterogeneity. In addition, there have been few linkages between the current growth of basic science research with animal models of AD and investigation of the possible explanations for the clinical variability. In this selected review, the principal recognized cognitive, motoric, and behavioral variations of AD are presented and how this heterogeneity might be investigated in animal models and other basic science approaches to AD is considered. Stage-related variability also is considered.
The purpose of this review is to stimulate dialogue between basic and clinical scientists regarding critical unresolved issues manifest at the clinical level and expressing important pathobiological aspects of the underlying disease.
Section snippets
Diagnosis of Alzheimer’s disease
Confidence in the diagnosis of AD is stratified according to definite, probable and possible levels [5]. Definite AD requires that the patient evidence the clinical syndrome of probable AD while alive and has biopsy or autopsy evidence consistent with AD. A diagnosis of probable AD is based on a typical clinical syndrome including gradual onset and progressive decline for at least six months in memory and at least one other cognitive domain in a patient who is not delirious and who has no other
Extrapyramidal variant of Alzheimer’s disease
Many patients with an AD-like syndrome and extrapyramidal dysfunction manifested by mild parkinsonism suffer from dementia with Lewy bodies (DLB) [26]. Some patients however, with AD and no evidence of Lewy bodies on autopsy, exhibit extrapyramidal syndromes during life. These patients have an increased number of neurofibrillary tangles and neuropil threads in the substantia nigra compared to patients with AD and no extrapyramidal signs [27]. Patients with AD and parkinsonism also have been
Stage-specific variability
Insidious onset and gradual progression are characteristic of AD. The rate of progression is relatively predictable and similar across different patient groups, but heterogeneity emerges when the rate of progression is compared among individuals. The stage of progression can be expressed numerically using rating scales such as the Global Deterioration Scale [32] or the Clinical Dementia Rating scale [33]. The decline in patients with advanced disease has been assessed using the Severe
Behavioral heterogeneity in Alzheimer’s disease
Behavioral alterations and neuropsychiatric symptoms may occasionally herald the onset of AD and these changes become steadily more frequent as the disease progresses. A wide range of noncognitive behavioral manifestations are observed in patients with AD. Depression is present in 25–50% of patients, disinhibition in 20–35%, delusions in 15–50%, hallucinations in 10–25%, agitation in 50–70%, anxiety in 30–50%, aggression in 25%, and sexual disinhibition in 5–10% [37], [38], [39], [40], [41],
Behavioral genetics of Alzheimer’s disease
Exploration of the behavioral genetics of AD is in its infancy. There has been limited attention to phenotypic differences in sporadic and autosomal dominant familial AD. In one study, Lahtovirta et al. [119] found no differences in either cognitive deficits or neuropsychiatric symptoms in patients with sporadic and familial AD.
The influence of the E-4 allele on cognition and behavior has been studied more extensively. The presence of the E-4 allele may result in more severe impairments of
Functional imaging assessment of transmitter system activity
Much can be learned from applying neuroimaging techniques to study cognitive and behavioral heterogeneity in AD. Positron emission tomography and SPECT have been used to assess the integrity of neuro-transmitter systems in normal control subjects and in patients with a variety of neurologic and psychiatric illnesses [132], [133], [134]. Properties of pharmacological agents can be assessed by labeling the agent itself and studying its anatomic distribution in the brain of normals compared to
Experimental models of cognitive and behavioral changes in Alzheimer’s disease
Animal models of AD can provide insight into the neurobiological bases and pathogenic mechanisms of cognitive and behavioral changes in AD patients. Studies have focused primarily on the pathologic changes of the animals with only limited attention to the cognitive changes and almost no investigation of changes in behaviors analogous to the neuropsychiatric symptoms commonly observed in AD. Monitoring of behavioral changes in animal models could both provide insight into the neurobiology of
Assessment of psychotropic effects of drugs in animal models of Alzheimer’s disease
Alzheimer’s disease research is mission-oriented and focused on the development of treatments that will prevent, defer the onset, slow the progress, or improve the cognitive and behavioral symptoms of AD. Animal models may have a role in assessing disease-modifying, mechanism-based, and symptomatic interventions. Disease-modifying treatments are those that ameliorate the central pathogenic events such as amyloid production, accumulation, or aggregation; inflammation; tau hyperphosphorylation
Summary
This review of the cognitive and behavioral diversity of AD provides a framework for a dialogue between basic and clinical scientists regarding animal models and the human form of AD. Basic science investigators may reveal causes of selective regional vulnerability in neurons providing an explanation for the cognition and behavioral heterogeneity absent in AD. Advances in treatment — disease-modifying, mechanism-based, and symptomatic — depend on advances in basic science research, improvement
Acknowledgments
This project was supported by an Alzheimer’s Disease Research Center grant (AG 16570) from the National Institute on Aging, an Alzheimer’s Disease Research Center of California grant, and the Sidell-Kagan Foundation.
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