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Heterogeneity in Alzheimer's Disease

M A R S H A L F. F O L S T E I N

The Johns Hopkins University School of Medicine, Baltimore, MD

The phenotype of Alzheimer's disease is variable. Age of onset, cognitive features, and neuropathology differ case to case. In some cases the differences are due to variable expression and others to genetic heterogeneity. Present evidence suggests four types of Alzbeimer's disease: early and late onset autosomal dominant forms, trisomy 21, and phenocopies.

THE discovery of the environmental and the genetic causes of Alzheimer's disease depends on the detection of Alzheimer's disease through its clinical and pathological features. However, cases differ in their clinical and pathological features. The number and type of signs required for diagnosis will determine the diagnostic subgroups to be used in risk factor and segregation and linkage analysis. Thus, if more symptoms were required for diagnosis such as amnesia and aphasia, then different cases would be selected than if fewer symptoms were required. The importance of the appropriate selection of phenotypic features to define cases is illustrated by the example of phenyLketonuria. Observation of hair color or intelligence does not clearly distinguish phenylke- tonurics from the general population, but the measurement of urine ketones does. Three phenotypic features that show heterogeneity in Alzheimer's disease are the cognitive syndrome, the age of onset, and the neuropathology.

THE COGNITIVE SYNDROME

The cognitive syndrome of amnesia, aphasia, apraxia, and agnosia (anna) has been recognized to be part of Alzheimer's disease in descriptions even before Alzheimer's. J. C. Pritchard

and others recognize that the syndrome now called probable Alzheimer's disease is something more than a prominent toss of memory. Cognitive features can be used to divide the population into subgroups. For example, studies of aphasia in Alzbeimer's disease have suggested that this feature may characterize a subgroup of patients with early onset of dementia and increased rate of progression of disease. The presence of amnesia, aphasia, apraxia, and agnosia indicates differences in the distribution of plaques and tangles in Alzheimer's disease. The complete syn- drome of amnesia, aphasia, apraxia, and agnosia indicates higher risk for dementia in the relatives of probands than in the relatives of individuals with a normal mental state or with amnesia alone. Recent studies indicate that NINCDS/ADRDA criteria for Atzhe- imer's disease which do not specify amnesia, aphasia, apraxia. and agnosia, but only that multiple cognitive defects be present, also identify a population whose first degree relatives are at approximately 50% risk.

AGE OF ONSET

Another aspect of phenotypic heterogeneity in Alzheimer's

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disease is age of onset, The age of onset in Alzheimer's disease has been shown to relate to the severity of language disturbance, the platelet membrane fluidity, and finger print pattern, the risk to relatives and also the severity of the neuropathology. The early onset cases are more severe. Early age of onset has been associated with genetic forms of Alzheimer's disease such as those linked to chromosome 21 and those associated with trisomy 21. Under- standing the mechanisms which determine the age of onset and its related features will be as important as the discovery of the genes responsible for the disease itself because delay of age of onset could eliminate the expression of Alzheimer's disease in human populations.

THE SEVERITY OF NEUROPATHOLOGY

Another important aspect of heterogeneity in the phenotypic features is in the neuropathology. Approximately 10% of cases

suffering from the syndrome of Alzheimer's disease have an unusual neuropathological expression such as cortical atrophy in the absence of significant plaques and tangles. Whether this entity should be regarded as variable expression or true heterogeneity remains to be determined.

In summary, the work of the last decade suggests that there are at least four types of Alzheimer's disease. First is an early onset form which is an autosomal dominant linked to chromosome 21. The second is Alzheimer's disease as it occurs in trisomy 21. The third type is a late onset form which, according to life table analysis is possibly an autosomal dominant form and finally there are probably cases which are phenocopies, environmentally deter- mined.

Advances in the search for the genes that cause Alzheimer's disease undoubtedly will depend on new refinement and measure- ment of the phenotypic features both clinically and pathologically as well as advances in the molecular technology which will lead to the isolation of the gene in those cases already linked.

Familial Alzheimer's Disease: Genetic Analysis Related to Disease Heterogeneity, Down Syndrome and Human Brain Evolution

M A R K B. S C H A P I R O A N D S T A N L E Y I. R A P O P O R T

Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892

Etiologically heterogeneous subgroups of patients with Alzheimer's disease (AD) exist and need to be distinguished so as to better identify genetic causes of familial cases. Furthermore, the presence of AD neuropathology in Down syndrome (trisomy 21) subjects older than 35 years suggests that AD in some cases is caused by dysregulation of expression of genes on chromosome 21. Cerebral metabolic abnormalities in life, and the distribution of AD neuropathology in the post-mortem brain, indicate that AD involves the association neocortices and subcortical regions with which they evolved during evolution of the human brain. Accordingly, understanding the molecular basis of this evolution should elucidate the genetic basis of AD, whereas knowing the genetics of AD should be informative about the genomic changes which promoted brain evolution.

AS pointed out by St. George-Hyslop et al. (13), a problem in genetic studies of Alzheimer's disease (AD) is the possible etiologic heterogeneity of the disorder, including the uncertainty as to whether there are multiple genetic or nongenetic causes. Recent evidence suggests that AD is a clinically heterogeneous disorder and that specific subtypes exist. For example, a clinical subtype has been identified that is characterized by, in addition to cognitive impairment, early onset of disease, rapid progression, and extrapyramidal signs (Parkinson-like features of rigid muscle tone and slowness of movement) (3). This subtype, denoted as Extrapyramidal Dementia of the Alzheimer Type (EDAT), is accompanied by reduced homovanillic acid (HVA), a metabolic product of dopamine, in the cerebrosopinal fluid (CSF), as well-reduced CSF biopterin (a cofactor of tyrosine hydroxylase mediated dopamine synthesis), in addition to evidence of reduced central cholinergic function as noted also in non-EDAT patients. Post-mortem studies of three EDAT patients so far have demon- strated AD neuropathology without evidence of Parkinson's dis-

ease in one, AD and Parkinson degeneration in another, and system atrophy in the third [(3), Kumar et al., in preparation). Recognizing disorders of movement and specific neurochemical abnormalities should enhance diagnostic accuracy for the EDAT subtype, and should allow better selection in calculating LOD scores for remaining non-EDAT patients as well as for this subtype. Other clinical subtypes of AD exist, including AD with myoclonus, depression or frontal lobe features, and need to be identified in AD populations.

A human model of AD exists that avoids such problems as heterogeneity. Down syndrome (DS), trisomy 21, is a genetic disorder in which an extra portion of chromosome 21 leads to mental retardation, short stature, and other phenotypic abnormal- ities (15). DS subjects over 35 years of age demonstrate neuro- pathological and neurochemical defects post-mortem which are virtually indistinguishable from those found in brains of AD patients, as well as a universal cognitive deterioration and a 20-30% prevalence of dementia. In older DS subjects and AD