Robert Katzman

Clinical diagnosis of Alzheimer's disease Report of the NINCDS‐ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease

Clinical criteria for the diagnosis of Alzheimers disease include insidious onset and progressive impairment of memory and other cognitive functions. There are no motor, sensory, or coordination deficits early in the disease. The diagnosis cannot be determined by laboratory tests. These tests are important primarily in identifying other possible causes of dementia that must be excluded before the diagnosis of Alzheimers disease may be made with confidence. Neuropsychological tests provide confirmatory evidence of the diagnosis of dementia and help to assess the course and response to therapy. The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimers disease; these criteria will be revised as more definitive information becomes available.

The Lewy body variant of Alzheimer's disease: A clinical and pathologic entity

Thirty-six clinically diagnosed and pathologically confirmed Alzheimers disease (AD) patients included 13 with cortical and subcortical Lewy bodies (LBs). The patients with LBs appeared to constitute a distinct neuropathologic and clinical subset of AD, the Lewy body variant (LBV). The LBV group showed gross pallor of the substantia nigra, greater neuron loss in the locus ceruleus, substantia nigra, and substantia innominata, lower neocortical ChAT levels, and fewer midfrontal tangles than did the pure AD group, along with a high incidence of medial temporal lobe spongiform vacuolization. Analysis of neuropsychological tests from 9 LBV subjects and 9 AD patients matched for age and degree of dementia revealed greater deficits in attention, fluency, and visuospatial processing in the LBV group. Similar comparisons of neurologic examinations showed a significant increase in masked facies; in addition there was an increase in essential tremor, bradykinesia, mild neck rigidity, and slowing of rapid alternating movements in the LBV group. Extremity rigidity, flexed posture, resting tremor, or other classic parkinsonian features were not characteristic of the LBV patient. In some cases, it may be possible to diagnose LBV premortem on the basis of the clinical and neuropsychological features.

Education and the prevalence of dementia and Alzheimer's disease.

Alzheimer’s disease (AD) is a democratic process. Physicians and psychologists, chess masters and physicists, mathematicians and musicians may become victims of this disorder. A poignant example that reached the national press was the obituary of George Beadle, a pioneer of biochemical genetics (whose experiments with mutations in the mold Neurospora crassa established the “one gene, one enzyme” relationship), a Nobel Laureate and later President of the University of Chicago, who died in 1989 of A D . I Yet a number of recent community studies report that individuals with lack of education or low education are more likely to develop dementia and AD. This finding has profound social and biological as well as medical implications. The effect of no or low education on the prevalence of dementia confirms the 1988 prediction of Mortimer2 that education would provide protection against dementia. He s ta ted (page 39) t h a t “psychosocial factors act primarily to reduce the margin of intellectual reserve to a level where a more modest level of brain pathology results in a d i a g no s a b 1 e dementia. ” He h y p o t h e s i ze d tha t “psychosocial risk factors will have their strongest associations in late-onset DAT of mild to moderate severity and . . . that low premorbid intelligence hastens the clinical diagnosis of DAT.” During the past 3 years the results of several epidemiologic studies have in part confirmed these predictions. Moreover, the recent finding that a close relationship exists between neocortical synaptic density and cognitive decline in AD provides a biological stratum for the postulated “intellectual reserve.” Our attention was focused on this risk factor by a population survey of dementia carried out in Shanghai in 1987.394 This was a two-stage survey of 5,055 subjects over age 55, stratified so that about one-third were 55 to 64, one-third 65 to 75, and one-third over the age of 75. The diagnosis of dementia was made after detailed clinical evaluation and was based on criteria in the third edition of the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association (DSM-III).5 Two-thirds of those diagnosed as demented met the clinical requirements of the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer’s Disease and Related Disorders Association (ADRDA) criteria for AD.6 An unexpected finding in the Shanghai survey was that lack of education is a major risk factor for and a major determinant of the prevalence of dementia.7 The Shanghai elderly differ from those in the United States in that 26.7% of the sample had never been to school and were not only illiterate but many could not carry out such presumably simple tasks as copying the overlapping pentagon figure of t he Mini-Mental S t a t e Examination (MMSE ),8 having had no childhood experience with a pen, pencil, o r brush.3 Another 36.7% had received 1 to 6 years of elementary education, many only 1 t o 2 years; and 36.1% had middle school or greater (some with doctoral degrees), a very wide spread in the educational spectrum. In subjects over the age of 75, there was a striking increase in the prevalence of clinically diagnosed dementia in those with no or low education. Adjusting for age in a multivariate analysis, the relative risk of developing dementia was approximately twice for those with no education as compared with those who had attended middle school and for those with elementary school education. Similar results have been obtained in subsequent surveys of dementia in southwestern F r a n ~ e , ~ Appignano, Italy,loJ1 Stockholm, Sweden,12 Finland,13 and Ashkelon, 1~rae l . l~

A CHINESE VERSION OF THE MINI-MENTAL STATE EXAMINATION; IMPACT OF ILLITERACY IN A SHANGHAI DEMENTIA SURVEY

A dementia screening survey was carried out in Shanghai using a culturally adapted Chinese version of the Mini-Mental State Examination. A probability sample of 5055 community-dwelling elderly in Shanghai was surveyed, 1497 aged 55-64, 2187 aged 65-74, and 1371 aged 75 and over. In the 73.3% of the subjects who had gone to school, using the age and education adjustments suggested by Kittner et al. (1986), [Kittner et al. J Chron Dis 39: 163-170; 1986] suitable cutoff scores could readily be selected to identify the subjects who should be examined intensively for the presence of dementia. However, in the 26.7% who had not gone to school, there was a significant increase in low scores on the mental status test as well as a different error pattern, reflecting the lack of formal education. Methods for following cognitive changes in illiterate individuals need further development.

Genetic association of the low-density lipoprotein receptor-related protein gene (LRP), and apolipoprotein E receptor, with late-onset Alzheimer's disease

The presence of the APOE ϵ4 allele encoding apolipoprotein E4 (apoE4) is the major genetic risk factor for late-onset Alzheimers disease (AD). However, the molecular and cellular mechanisms by which APOE ϵ4 renders AD risk are unclear. In this report, we present genetic evidence that an apoE receptor, LRP, may be associated with the expression of late-onset AD. Using a biallelic genetic marker in exon 3 LRP, late-onset AD cases markedly differed from the control subjects in the distribution of LRP genotypes, and this difference was highly accentuated among AD cases with positive family history of senile dementia. Furthermore, the numbers of neuritic plaques were significantly altered as a consequence of different LRP genotypes in postmortem AD cases. Taken together, our results implicate the pathophysiology of LRP in the expression of late-onset AD.

Modulation of amyloid β-protein clearance and Alzheimer’s disease susceptibility by the LDL receptor–related protein pathway

Susceptibility to Alzheimers disease (AD) is governed by multiple genetic factors. Remarkably, the LDL receptor-related protein (LRP) and its ligands, apoE and alpha2M, are all genetically associated with AD. In this study, we provide evidence for the involvement of the LRP pathway in amyloid deposition through sequestration and removal of soluble amyloid beta-protein (Abeta). We demonstrate in vitro that LRP mediates the clearance of both Abeta40 and Abeta42 through a bona fide receptor-mediated uptake mechanism. In vivo, reduced LRP expression is associated with LRP genotypes and is correlated with enhanced soluble Abeta levels and amyloid deposition. Although LRP has been proposed to be a clearance pathway for Abeta, this work provides the first in vivo evidence that the LRP pathway may modulate Abeta deposition and AD susceptibility by regulating the removal of soluble Abeta.

Senile Dementia of the Alzheimer Type Without Neocortical Neurofibrillary Tangles

Senile dementia of the Alzheimer type (SDAT) is typified pathologically by neuritic plaques (NP) and neurofibrillary tangles (NFT) in the neocortex and hippocampus. However, in a large series of cases (60) over age 74 a significant minority (30%) lacked neocortical tangles. In order to determine if these latter cases (Group B) otherwise differ from the majority which have both neocortical plaques and tangles (Group A), various clinical and neuropathological parameters were measured for both groups and the results compared. The following indices were examined: degree of dementia, rate of progression of dementia, age at death, brain weight, cerebral hemispheric weight, cortical cell counts from the frontal, temporal, and parietal lobes, the number of neocortical NP, the number of hippocampal NP and NFT, and the levels of neocortical choline acetyltransferase and somatostatin. The two groups showed no statistically significant differences in any of these categories except for increased numbers of neocortical NP in Group A in midfrontal and superior temporal regions. However, cases in Group A showed greater pathologic abnormality in nearly every parameter, albeit without attaining statistical significance. We conclude that SDAT with neocortical NFT is the same disease as SDAT without them, although the presence of such tangles is associated with a tendency towards greater severity.

Cognitive decline is faster in Lewy body variant than in Alzheimer's disease

Objectives: To quantify the rate of cognitive decline on the Mini-Mental State Examination (MMSE) in autopsy-diagnosed Lewy body variant (LBV) of Alzheimers disease (AD) cases. We hypothesized that LBV patients would have a faster cognitive decline and shorter survival compared with patients with pure AD. Background: Prior reports have shown extrapyramidal signs to be associated with a poorer prognosis in AD. It has been suggested that LBV is often characterized by a rapidly progressive course. Few data are available regarding the rate of cognitive decline in autopsy-confirmed LBV dementia cases. Methods: We searched the databases of the University of California-San Diego Alzheimers Disease Research Center and the Consortium to Establish a Registry in Alzheimers Disease (CERAD) for dementia cases with 1) an autopsy diagnosis of definite or probable AD (CERAD criteria) with concomitant Lewy bodies and 2) longitudinal MMSE assessments. This resulted in a series of 40 LBV cases and 148 AD cases without Lewy bodies, with comparable baseline MMSE scores, age, and education. The rate of cognitive decline was calculated as the baseline MMSE - final MMSE. Methods were devised to reduce floor effects on the MMSE. Results: The average rate of cognitive decline was -5.8 ± 4.5 points/y in LBV and -4.1 ± 3.0 points/y in AD (t-test, p< 0.01). The LBV group declined a similar amount on the MMSE (means, -10.0 versus -9.6 points) over a significantly shorter time interval (1.9 versus 2.7 years; p = 0.005) than did AD patients. At baseline, the mean MMSE scores were nearly identical (18.2 in LBV; 17.8 in AD), but on follow-up examinations approximately 1, 2, and 3 years later, there were intergroup mean differences of 1.8 points (two-tailed p = 0.19), 4.2 points (p = 0.04), and 5.6 points (p = 0.03), respectively. The LBV cases had shorter survival time from the onset of cognitive symptoms (7.7 ± 3.0 years versus 9.3 ± 3.5 years; p = 0.007) and a shorter mean survival after entry/baseline, which was of marginal significance (3.6 versus 4.1 years; p = 0.11). Conclusions: This study demonstrates that LBV is characterized by a faster cognitive decline and accelerated mortality compared with AD.

Women, myocardial infarction, and dementia in the very old

Dementia is a major public health problem among the very old. Available information on incidence and prevalence is sparse and variable; however, there appears to be a higher prevalence among very old women. We present data from a prospective study of initially nondemented community-residing elderly. There were 75 incident dementia cases (up to 7 years of follow-up) of which at least 47% were probable Alzheimers disease. Based on a proportional hazards analysis, women were over 3 times more likely to develop dementia than men despite controlling for baseline demographic, psychosocial, and medical history variables. Poor word fluency and a high normal Blessed test score at baseline were also strong predictors of dementia. We did not find age, head trauma, thyroid disease, or family history of dementia to be risk factors. A new finding is that history of myocardial infarction (MI) is associated with dementia, such that women with a history of MI were 5 times more prone to dementia than those without a history. This observation was not true for men.

The apolipoprotein E epsilon 4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimer's disease and Lewy body variant

Objective: To determine the relationship between apolipoprotein E (apoE) genotype and neuropathologic lesions in Alzheimers disease (AD) and Lewy body variant (LBV). Design: Retrospective genetic-neuropathologic study of AD and LBV cases. The main neuropathologic outcome measures were modeled as a function of apoE genotype, neuropathologic diagnosis, and gender. Age at death and duration of symptom effects were controlled for by ANCOVA. Patients: One hundred twenty-seven cases with neuropathologically diagnosed AD (n = 84) or LBV (n = 43). Main outcome measures: Quantitative scores of neuritic plaques (NPs), neurofibrillary tangles (NFTs), cerebral amyloid angiopathy (CAA) severity, and CAA prevalence were averaged across four brain regions: midfrontal, inferior parietal, superior temporal, and hippocampal. Results: The apoE epsilon 4 allele was associated with increased NPs within both AD and LBV. The epsilon 4 allele was associated with an increased frequency of CAA in the AD and LBV groups combined and in LBV alone. While CAA severity and NFTs were increased in the epsilon 4/4 homozygous cases when AD and LBV were combined, there were no significant effects within AD or LBV alone. Conclusions: The apoE epsilon 4 allele is strongly associated with increased NPs, but not neocortical NFTs, in both AD and LBV. NEUROLOGY 1996;47: 190-196