Elsevier

Neurobiology of Aging

Volume 21, Issue 6, November–December 2000, Pages 845-861
Neurobiology of Aging

Open peer commentary
Cognitive and behavioral heterogeneity in Alzheimer’s disease: seeking the neurobiological basis

https://doi.org/10.1016/S0197-4580(00)00183-4Get rights and content

Abstract

Alzheimer’s disease (AD) is manifested by core features of progressive memory impairment, visuospatial decline, aphasia, and loss of executive function. In addition, patients may evidence a variety of other cognitive and behavioral features. The neurobiological basis for this clinical heterogeneity is uncertain but corresponding abnormalities on functional imaging suggest that variations in the distribution of the pathogenic changes in AD account for some of the observed clinical differences. Behavioral as well as cognitive variability has been correlated with disturbances on positron emission tomography and single photon emission computerized tomography. Functional imaging can reveal characteristic brain activity changes in AD, distinguish AD from other dementia syndromes, assess the integrity of transmitter systems in AD, determine the effect of cognitive enhancing and psychotropic drugs on metabolism and transmitter system function in AD, and possibly predict treatment responsiveness. Animal models of AD may improve our understanding of clinical variations in human AD. Thus far, development of cognitive tests for transgenic mice with AD pathology has been limited. Evaluations paralleling human neuropsychological tests are needed. In addition, technologies facilitating behavioral observations relevant to psychosis, depression, apathy, and agitation in AD have not been developed for transgenic models. Application of experiments inducing animal equivalents of depression and psychosis to determine the vulnerability of animal models of AD to these conditions may provide additional insights into human neuropsychiatric symptoms in AD. The efficacy of psychotropic drugs can be assessed in animal models of AD subjected to the provocative stimuli used in experimental models of psychopathology. There are a plethora of opportunities for basic scientists to offer insights, develop strategies, and provide techniques and technologies relevant to understanding the clinical manifestations of AD.

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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