Background

This is the most common cause of dementia in the elderly population. Currently 4 million Americans have Alzheimer disease (AD). The pathogenesis has eluded researchers for many years, but finally, there is light. Two histologic changes are characteristic for the disease, amyloid plaques and neurofibrillary tangles. The changes begin in the hippocampus of the brain and spread to other parts of the central nervous system.

The clinical presentation is familiar to most of us. It is a slowly progressive and irreversible dementia. Memory loss, decreased cognitive function, altered behavior, and loss of the ability to perform activities of daily living are all part of this relentless disease.

The two most active areas of research are treatments and a laboratory test which may detect the disease in asymptomatic individuals. The outline below highlights some of the latest research in both of these areas.

OUTLINE

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
INCIDENCE	10% of patients >65 years Up to 50% of patients>85 years About 17-24 million worldwide are affected with about 4 million affected in the United States Fourth leading cause of death in Western Countries
AGE RANGE-MEDIAN
65-74 years	3% rate
75-84 years	19%
85 years or more	47%

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
GENERAL
Comorbidity in dementia: an autopsy study. Fu C, Chute DJ, Farag ES, Garakian J, Cummings JL, Vinters HV. Section of Neuropathology, University of California, Los Angeles (UCLA) Medical Center and David Geffen School of Medicine at UCLA, 090095-1732, USA.	Arch Pathol Lab Med. 2004 Jan;128(1):32-8. Abstract quote   CONTEXT: There is a paucity of accurate postmortem data pertinent to comorbid medical conditions in patients with dementia, including Alzheimer disease. OBJECTIVES: The purposes of this study were (a) to examine general autopsy findings in patients with a dementia syndrome and (b) to establish patterns of central nervous system comorbidity in these patients. DESIGN: Review of autopsy reports and selected case material from 202 demented patients who had "brain-only" autopsies during a 17-year period (1984-2000) and from 52 demented patients who had general autopsies during a 6-year period (1995-2000). SETTING: Large academic medical center performing approximately 200 autopsies per year. RESULTS: Among the 52 patients who underwent complete autopsy, the most common cause of death was bronchopneumonia, which was found in 24 cases (46.1%). Other respiratory problems included emphysema, found in 19 (36.5%) of 52 patients, and pulmonary thromboembolism, found in 9 (17.3%) of 52 patients. In 6 cases, pulmonary thromboembolism was the proximate cause of death. Twenty-one (40.3%) of the 52 patients had evidence of a myocardial infarct (varying ages) and 38 (73.1%) had atherosclerotic cardiovascular disease, 27 of a moderate to severe degree. Four clinically unsuspected malignancies were found: 1 each of glioblastoma multiforme, diffusely infiltrative central nervous system lymphoma, pancreatic adenocarcinoma, and adenocarcinoma of the lung. One patient with frontotemporal dementia and amyotrophic lateral sclerosis died of severe meningoencephalitis/ventriculitis, probably secondary to seeding of the central nervous system by an infected cardiac valve. Of the 202 demented patients who underwent brain-only autopsies, the following types of dementia were found: 129 (63.8%) cases showed changes of severe Alzheimer disease, 21 (10.4%) showed combined neuropathologic abnormalities (Alzheimer disease plus another type of lesion, such as significant ischemic infarcts or diffuse Lewy body disease), 12 (5.9%) cases of relatively pure ischemic vascular dementia, 13 (6.4%) cases of diffuse Lewy body disease, and 8 (4.0%) cases of frontotemporal dementia. The remaining 19 (9.4%) patients showed miscellaneous neuropathologic diagnoses, including normal pressure hydrocephalus and progressive supranuclear palsy. Among the demented patients, 92 (45.5%) had cerebral atherosclerosis, which was moderate to severe in 65 patients (32.2%). CONCLUSIONS: Some of the conditions found at autopsy, had they been known antemortem, would likely have affected clinical management of the patients. Autopsy findings may be used as a quality-of-care measure in patients who have been hospitalized in chronic care facilities for a neurodegenerative disorder.
HORMONE REPLACEMENT THERAPY
Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. Espeland MA, Rapp SR, Shumaker SA, Brunner R, Manson JE, Sherwin BB, Hsia J, Margolis KL, Hogan PE, Wallace R, Dailey M, Freeman R, Hays J; Women's Health Initiative Memory Study. Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.	JAMA. 2004 Jun 23;291(24):2959-68. Abstract quote CONTEXT: The Women's Health Initiative Memory Study (WHIMS) previously reported that estrogen plus progestin therapy does not protect cognition among women aged 65 years or older. The effect of estrogen-alone therapy, also evaluated in WHIMS, on cognition has not been established for this population. OBJECTIVES: To determine whether conjugated equine estrogen (CEE) alters global cognitive function in older women and to compare its effect with CEE plus medroxyprogesterone acetate (CEE plus MPA). DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled ancillary study of the Women's Health Initiative (WHI), WHIMS evaluated the effect of CEE on incidence of probable dementia among community-dwelling women aged 65 to 79 years with prior hysterectomy from 39 US academic centers that started in June 1995. Of 3200 eligible women free of probable dementia enrolled in the WHI, 2947 (92.1%) were enrolled in WHIMS. Analyses were conducted on the 2808 women (95.3%) with a baseline and at least 1 follow-up measure of global cognitive function before the trial's termination on February 29, 2004. INTERVENTIONS: Participants received 1 daily tablet containing either 0.625 mg of CEE (n = 1387) or matching placebo (n = 1421). MAIN OUTCOME MEASURE: Global cognitive function measured annually with the Modified Mini-Mental State Examination (3MSE). RESULTS: During a mean follow-up of 5.4 years, mean (SE) 3MSE scores were 0.26 (0.13) units lower than among women assigned to CEE compared with placebo (P =.04). For pooled hormone therapy (CEE combined with CEE plus MPA), the mean (SE) decrease was 0.21 (0.08; P =.006). Removing women with dementia, mild cognitive impairment, or stroke from the analyses lessened these differences. The adverse effect of hormone therapy was more pronounced among women with lower cognitive function at baseline (all P<.01). For women assigned to CEE compared with placebo, the relative risk of having a 10-unit decrease in 3MSE scores (>2 SDs) was estimated to be 1.47 (95% confidence interval, 1.04-2.07). CONCLUSION: For women aged 65 years or older, hormone therapy had an adverse effect on cognition, which was greater among women with lower cognitive function at initiation of treatment.
Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, Fillit H, Stefanick ML, Hendrix SL, Lewis CE, Masaki K, Coker LH; Women's Health Initiative Memory Study. Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.	JAMA. 2004 Jun 23;291(24):2947-58. Abstract quote   CONTEXT: The Women's Health Initiative Memory Study (WHIMS) previously found increased risk for dementia and no effect on mild cognitive impairment (MCI) in women treated with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA). OBJECTIVE: To determine the effects of CEE alone and CEE plus MPA on incidence of probable dementia and MCI in older women. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled clinical trials of CEE (estrogen-alone trial) or CEE plus MPA (estrogen plus progestin trial) in community-dwelling women aged 65 to 79 years, conducted from June 1995 to July 8, 2002 (estrogen plus progestin; n = 4532), or to February 29, 2004 (estrogen-alone; n = 2947), in 39 of the 40 WHI clinical centers. INTERVENTIONS: In the estrogen-alone trial, 1 daily tablet containing either 0.625 mg/d of CEE vs matching placebo; in the estrogen plus progestin trial, 1 daily tablet containing CEE (0.625 mg/d) plus MPA (2.5 mg/d) vs matching placebos. MAIN OUTCOME MEASURES: Probable dementia and MCI. RESULTS: In the estrogen-alone trial, 47 participants were diagnosed with probable dementia, of whom 28 were assigned to CEE and 19 to placebo (hazard ratio [HR], 1.49; 95% confidence interval [CI], 0.83-2.66). Incidence rates for probable dementia in the estrogen-alone trial were statistically similar to those in the estrogen plus progestin trial (45 vs 22 per 10 000 person-years for CEE plus MPA vs placebo, respectively; P =.11). When data were pooled per the original WHIMS protocol, the overall HR for probable dementia was 1.76 (95% CI, 1.19-2.60; P =.005). After excluding participants with baseline Modified Mini-Mental State Examination scores at or below the screening cut point, the HR was 1.77 (95% CI, 0.74-4.23; P =.20) in the estrogen-alone trial and 2.19 (95% CI, 1.25-3.84; P =.006) in the pooled trials. In the estrogen-alone trial, 76 participants were diagnosed with MCI in the CEE group vs 58 in the placebo group (HR, 1.34; 95% CI, 0.95-1.89). In the combined trial data, the HR was similar (1.25; 95% CI, 0.97-1.60). In the estrogen-alone trial, 93 participants receiving CEE were diagnosed with either probable dementia or MCI vs 69 receiving placebo (HR, 1.38; 95% CI, 1.01-1.89; P =.04). CONCLUSIONS: Estrogen therapy alone did not reduce dementia or MCI incidence and increased the risk for both end points combined. Pooling data for estrogen alone and estrogen plus progestin resulted in increased risks for both end points. Use of hormone therapy to prevent dementia or cognitive decline in women 65 years of age or older is not recommended.
Hormone replacement therapy and incidence of Alzheimer disease in older women: the cache county study. Zandi PP, Carlson MC, Plassman BL, Welsh-Bohmer KA, Mayer LS, Steffens DC, Breitner JC. GRECC (S-182), VA Puget Sound Health Care System, 1660 S Columbian Way, Seattle, WA 98108.	JAMA 2002 Nov 6;288(17):2123-9 Abstract quote CONTEXT: Previous studies have shown a sex-specific increased risk of Alzheimer disease (AD) in women older than 80 years. Basic neuroscience findings suggest that hormone replacement therapy (HRT) could reduce a woman's risk of AD. Epidemiologic findings on AD and HRT are mixed. OBJECTIVE: To examine the relationship between use of HRT and risk of AD among elderly women. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of incident dementia among 1357 men (mean age, 73.2 years) and 1889 women (mean age, 74.5 years) residing in a single county in Utah. Participants were first assessed in 1995-1997, with follow-up conducted in 1998-2000. History of women's current and former use of HRT, as well as of calcium and multivitamin supplements, was ascertained at the initial contact. MAIN OUTCOME MEASURE: Diagnosis of incident AD. RESULTS: Thirty-five men (2.6%) and 88 women (4.7%) developed AD between the initial interview and time of the follow-up (3 years). Incidence among women increased after age 80 years and exceeded the risk among men of similar age (adjusted hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.22-3.86). Women who used HRT had a reduced risk of AD (26 cases among 1066 women) compared with non-HRT users (58 cases among 800 women) (adjusted HR, 0.59; 95% CI, 0.36-0.96). Risk varied with duration of HRT use, so that a woman's sex-specific increase in risk disappeared entirely with more than 10 years of treatment (7 cases among 427 women). Adjusted HRs were 0.41 (95% CI, 0.17-0.86) for HRT users compared with nonusers and 0.77 (95% CI, 0.31-1.67) compared with men. No similar effect was seen with calcium or multivitamin use. Almost all of the HRT-related reduction in incidence reflected former use of HRT (9 cases among 490 women; adjusted HR, 0.33 [95% CI, 0.15-0.65]). There was no effect with current HRT use (17 cases among 576 women; adjusted HR, 1.08 [95% CI, 0.59-1.91]) unless duration of treatment exceeded 10 years (6 cases among 344 women; adjusted HR, 0.55 [95% CI, 0.21-1.23]). CONCLUSIONS: Prior HRT use is associated with reduced risk of AD, but there is no apparent benefit with current HRT use unless such use has exceeded 10 years.

 

PATHOGENESIS	CHARACTERIZATION
Loss of cholinergic neurons	People with AD gradually lose their cholinergic neurons
Apolipoprotein E gene	N Engl J Med 2000;343:450-456 The apolipoprotein E gene (APOE) is a risk factor in both EOAD and LOAD The epsilon 4 allele further increases this risk-patients with this allele had greater brain activation than epsilon 3 allele homozygotes indicating that these brains had to work harder to complete the same task-may work by enhancing Abeta aggregation or decreasing clearance in the brain, rather than increasing production
Genotypes and phenotypes for apolipoprotein E and Alzheimer disease in the Honolulu-Asia aging study. Kardaun JW, White L, Resnick HE, Petrovitch H, Marcovina SM, Saunders AM, Foley DJ, Havlik RJ. Archa B.V., 3039 HK Rotterdam, The Netherlands.	Clin Chem 2000 Oct;46(10):1548-54 Abstract quote BACKGROUND: The utility of apolipoprotein E (ApoE) type as an indicator of genetic susceptibility to Alzheimer disease (AD) depends on the reliability of typing. Although ApoE protein isoform phenotyping is generally assumed equivalent to genotyping from DNA, phenotype-genotype differences have been reported. METHODS: ApoE genotype and phenotype results were examined for 3564 older (ages 71-93 years) Japanese-American male participants of the Honolulu-Asia Aging Study, an ongoing population-based study of aging and dementia. RESULTS: Both methods demonstrated similar associations of ApoE type with AD: a direct association with ApoE4 and a less dramatic inverse association ApoE2. Advanced age did not appear to influence the ApoE4-AD association. The association with AD among ApoE4 homozygotes [odds ratio (OR) = 14.7] was higher than expected based on an observed OR of 2.0 in heterozygotes. Phenotype-genotype nonconcordance was more frequent for ApoE2 than for ApoE4. The ApoE2 phenotype occurred at a frequency of 7.9% vs a genotype frequency of 4.9%, corresponding to a probability of 56% that an individual with ApoE2 phenotype had the same genotype. CONCLUSIONS: Whereas E4 and E2 phenotypes and genotypes were comparably associated with AD, neither method would be expected to substantially improve the efficiency of case finding in the context of population screening beyond prediction based on age and education. Nonconcordance of phenotype and genotype was substantial for E2 and modest for E4 in this population. The ApoE4-AD association was independent of age.
Abeta42	Generated from the Alzheimer amyloid precursor protein (APP) in two consecutive cleavage events: Beta-secretase (proteolytic which generates the N-terminus of Abeta) Gamma-secretase (Generates the C-terminus) APP gene on chromosome 21 (same duplicated chromosome in Down's syndrome, these same patients are prone to develop Alzheimer's by age 50 years) Most Abeta peptides terminate at AA valine 40 or alanine 42 but the longer species Abeta42 is prone to aggregation and is the initial amyloid protien deposited in the plaques of Alzheimer's and Down's syndrome
Neurofibrillary tangles	Interneuronal inclusions of hyperphosphorylated tau protein which become concentrated in nerve cells, breaking down the tubules and accumulating
INHERITED FORMS	Three genes have identified in EOAD families Mutations in these genes enhance the cellular production of Abeta42 by selectively increasing the final cleavage of APP by gamma-secretase
APP	One APP mutation may increase the cleavage of beta-secretase
Presenilin 1 (PS1)	Proc Natl Acad Sci 2000;97:9299-9304. Suspected that this is the gamma-secretase
Presenilin 2 (PS2)
alpha-Synuclein in Familial Alzheimer Disease: Epitope Mapping Parallels Dementia With Lewy Bodies and Parkinson Disease. Lippa CF, Schmidt ML, Lee VM, Trojanowski JQ. Department of Neurology, Medical College of Pennsylvania-Hahnemann University, 3300 Henry Ave, Philadelphia, PA 19129.	Arch Neurol 2001 Nov;58(11):1817-1820 Abstract quote BACKGROUND: alpha-Synuclein is a major component of Lewy bodies (LBs) in Parkinson disease and dementia with LBs and of glial cytoplasmic inclusions in multiple system atrophy. However, epitope mapping for alpha-synuclein is distinctive in different neurodegenerative diseases. The reasons for this are poorly understood but may reflect fundamental differences in disease mechanisms. OBJECTIVE: To investigate the alpha-synuclein epitope mapping properties of LBs in familial Alzheimer disease. DESIGN AND SETTING: We compared LBs in familial Alzheimer disease with those in synucleinopathies by probing 6 brains of persons with familial Alzheimer disease using a panel of antibodies to epitopes spanning the alpha-synuclein protein. Results were compared with data from brains of persons with Parkinson disease, dementia with LBs, and multiple system atrophy. RESULTS: The brains of persons with familial Alzheimer disease showed consistent staining of LBs with all antibodies, similar to Parkinson disease and dementia with LBs but different from alpha-synuclein aggregates that occurred in multiple system atrophy. CONCLUSIONS: These data suggest that the epitope profiles of alpha-synuclein in LBs are similar, regardless of whether the biological trigger is related to synuclein or a different genetic pathway. These findings support the hypothesis that the mechanism of alpha-synuclein aggregation is the same within cell types but distinctive between cell types.
Susceptibility locus for Alzheimer's disease on chromosome 10. Myers A, Holmans P, Marshall H, Kwon J, Meyer D, Ramic D, Shears S, Booth J, DeVrieze FW, Crook R, Hamshere M, Abraham R, Tunstall N, Rice F, Carty S, Lillystone S, Kehoe P, Rudrasingham V, Jones L, Lovestone S, Perez-Tur J, Williams J, Owen MJ, Hardy J, Goate AM. Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid, St. Louis, MO 63110, USA.	Science 2000 Dec 22;290(5500):2304-5 Abstract quote The apolipoprotein E (APOE) gene is the only genetic risk factor that has so far been linked to risk for late-onset Alzheimer's disease (LOAD). However, 50 percent of Alzheimer's disease cases do not carry an APOE4 allele, suggesting that other risk factors must exist. We performed a two-stage genome-wide screen in sibling pairs with LOAD to detect other susceptibility loci. Here we report evidence for an Alzheimer's disease locus on chromosome 10. Our stage one multipoint lod score (logarithm of the odds ratio for linkage/no linkage) of 2.48 (266 sibling pairs) increased to 3.83 in stage 2 (429 sibling pairs) close to D10S1225 (79 centimorgans). This locus modifies risk for Alzheimer's disease independent of APOE genotype.
ESTROGEN RECEPTORS
Colocalization and alteration of estrogen receptor-alpha and -beta in the hippocampus in Alzheimer's disease. Lu YP, Zeng M, Swaab DF, Ravid R, Zhou JN.	Hum Pathol 2004;35:275-280 Abstract quote The human hippocampus is severely affected in Alzheimer's disease (AD). Because postmenopausal estrogen use may decrease the risk and delay the onset and progression of AD, possibly by a direct action on the hippocampal neurons, we used fluorescence immunocytochemistry to examine the colocalization of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) in the hippocampus of elderly human controls and AD patients. Double-labeling cells (DLCs) of ERalpha and ERbeta can be divided into 3 types: double-cytoplasm-staining cells (DCCs), double-nucleus-staining cells (DNCs), and ERalpha nucleus-staining and ERbeta cytoplasm-staining cells (NCCs). There was no difference in the percentage of DLCs in total ERalpha-positive cells or in total ERbeta-positive cells in the CA1 to CA4 subfields of the hippocampus between controls and AD patients. Interestingly, the ratio of DNCs to the total ERalpha-positive cells (2.6% +/- 0.5%) or to the total ERbeta-positive cells (1.8% +/- 0.3%) in the CA1 subfield of the AD hippocampus was significantly decreased in comparison with controls (5.0% +/- 0.7% and 3.9% +/- 0.6%, respectively; P < 0.001), suggesting that changes in the compartmentalization of these receptors could play a role in the pathogenesis of AD.

 

LABORATORY/ RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
Radiographs
CT scan and MRI
Cerebrospinal Fluid A42, Tau, and F2-Isoprostane Concentrations in Patients With Alzheimer Disease, Other Dementias, and in Age-Matched Controls Thomas J. Montine, etal.	Arch Pathol Lab Med 2001; 125:510–512. Objective.—To test the hypothesis that quantification of cerebrospinal fluid (CSF) F2-isoprostanes (F2-IsoPs), in vivo biomarkers of free radical damage, along with CSF A42 and tau levels improves laboratory diagnostic accuracy for Alzheimer disease (AD). Participants.—Patients with probable AD (n = 19), dementias other than AD (n = 8), and age-matched controls (n = 10). Main Outcome Measures.—Cerebrospinal fluid concentrations of A42 and tau were determined by a commercially available test (Athena Diagnostics, Worcester, Mass). Cerebrospinal fluid F2-IsoP levels were quantified by gas chromatography/mass spectrometry. Results.—Individuals were classified as AD or non-AD by a published method using CSF A42 and tau levels (95% sensitivity, 50% specificity), by CSF F2-IsoP levels greater than 25 pg/mL and A42 concentrations less than 1125 pg/mL (90% sensitivity, 83% specificity), and by combined analysis using CSF F2-IsoP, A42, and tau levels (84% sensitivity, 89% specificity). Conclusion.—Cerebrospinal fluid F2-IsoP quantification may enhance the accuracy of the laboratory diagnosis of AD.
LABORATORY
Decreased {beta}-Amyloid1-42 and Increased Tau Levels in Cerebrospinal Fluid of Patients With Alzheimer Disease. Sunderland T, Linker G, Mirza N, Putnam KT, Friedman DL, Kimmel LH, Bergeson J, Manetti GJ, Zimmermann M, Tang B, Bartko JJ, Cohen RM. Geriatric Psychiatry Branch, National Institute of Mental Health, Bethesda, Md.	JAMA 2003 Apr 23;289(16):2094-2103 Abstract quote CONTEXT: Alzheimer disease (AD) is characterized by pathological results at autopsy of amyloid plaques and tau-associated neurofibrillary tangles, but the clinical diagnosis of AD is determined on the basis of medical history, cognitive symptoms, and exclusionary criteria. The search for antemortem biomarkers is intense and has focused on cerebrospinal fluid (CSF) beta-amyloid1-42 and tau proteins. OBJECTIVES: To compare CSF beta-amyloid and tau levels in a new population of AD patients and controls. To perform a meta-analysis of studies of CSF beta-amyloid and tau levels in AD patients and controls. DESIGN: Cross-sectional study of the comparison of baseline CSF beta-amyloid1-42 and tau levels in AD patients and controls. Meta-analysis involved 17 studies of CSF beta-amyloid and 34 studies of CSF tau. SETTING: Clinical research unit of the National Institute of Mental Health, Bethesda, Md. PATIENTS: The Geriatric Psychiatry Branch evaluated AD patients as inpatients at the National Institutes of Health Clinical Center between May 1985 and January 2001. A total of 203 patients participated in this study (131 with AD and 72 controls). None had other serious illnesses, and 31 of 131 AD cases had AD confirmed at autopsy. Meta-analysis provided an additional 3133 AD patients and 1481 controls. MAIN OUTCOME MEASURES: Levels of CSF beta-amyloid1-42 were measured by a sandwich enzyme-linked immunoabsorbent assay with a polyclonal capture antibody and a monoclonal detection antibody. Levels of CSF tau were measured with a standard commercial immunoassay. RESULTS: Levels of CSF beta-amyloid1-42 were significantly lower in the AD patients vs controls (mean [SD], 183 [121] pg/mL vs 491 [245] pg/mL; P<.001). Levels of CSF tau were significantly higher in AD patients (mean [SD], 587 [365] pg/mL vs 244 [156] pg/mL; P<.001). The cutpoints of 444 pg/mL for CSF beta-amyloid1-42 and 195 pg/mL for CSF tau gave a sensitivity and specificity of 92% and 89%, respectively, to distinguish AD patients from controls, which is comparable with rates with clinical diagnosis. Meta-analyses of studies comparing CSF beta-amyloid and tau levels in AD participants and controls confirmed an overall difference between levels in these 2 groups. CONCLUSIONS: Alzheimer disease is associated with a significant decrease in CSF beta-amyloid1-42 levels along with an increase in CSF tau levels. These findings suggest that the 2 measures are biological markers of AD pathophysiology. While these CSF measures may have a potential clinical utility as biomarkers of disease, the preliminary and retrospective nature of the findings, the absence of assay standardization, and the lack of comparison patient populations must be addressed in future studies testing the usefulness of these CSF measures for predictive, diagnostic, or treatment evaluation purposes.
Laboratory Markers	Adapted from Clinical Laboratory News 2000;26:7 In general, there is a lack of standardization among assays and significant overlap between normal and abnormal results

Marker	CSF	Blood	Urine
Abeta42	x	x
Tau protein	x
Abeta42 and tau	x
AD7C-NTP	x		x
APOE (Apolipoprotein E)		x
p97		x
Platelet APP fragmentation		x

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
General	See Internet Links Classically, widening of the cerebral sulci in the frontal, temporal, and parietal lobes Secondary dilatation of the ventricular system
VARIANTS	5-10% cases are familial
Early onset Alzheimer's disease (EOAD)	Autosomal dominant with age-dependent penetrance Usually occurs <65 years
Late onset Alzheimer's disease (LOAD)	Usually occurs >65 years Inheritance pattern unclear

 

HISTOLOGICAL TYPES	CHARACTERIZATION
Pathologic Finding	Composition
Neuritic Amyloid plaques	Polymers of beta amyloid form the core, derived from APP Spherical collections of neuritic processes surrounding a central amyloid core, usually with a clear halo Hippocampus and amygdala and neocortex but usually spares the primary motor and sensory cortices
Diffuse plaques	Lack the neuritic processes and found in the superficial portions of the cortex and basal ganglia and cerebellar cortex
Neurofibrillary tangles	Bundles of filaments in the neuronal cytoplasm forming an elongated flame shape-stain positive with silver stains Hyperphosphorylated tau protein which destablilizes the microtubules in neurons. As the tubules break down, the phosphorylated proteins accumulate to become tangles Also contain MAP2 (microtubule-associated protein), ubiquitin, and amyloid beta peptide
Granulovacuolar degeneration	Small clear intraneuronal cytoplasmic vacuoles containing an argyrophilic granule Most common in hippocampus and olfactory bulb
Hirano bodies	Elongated glassy eosinophilic bodies composed of paracrystalline arrays of beaded filaments Actin is major component Found in hippocampal pyramidal cells

 

SPECIAL STAINS/ IMMUNOPEROXIDASE/ OTHER	CHARACTERIZATION
Special stains	Silver stains highlight the neuritic plaques and tangles Congo red stain highlights the amyloid deposits as well as the amyloid core of the neuritic plaque

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
Pick Disease
Neurofibrillary tangles	Also found in: Progressive supranuclear palsy Postencephalitic Parkinson disease Amyotrophic lateral sclerosis Parkinsonism/dementia complex of Guam

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS
Survival	Relentless course with final stagesof incontinence, loss of mobility, and mute Pneumonia or other intercurrent disease is usual cause of death
TREATMENT	Rivastigmine (Exelon) Rivastigmine belongs to the same class of drugs as donepezil (Aricept) and tacrine (Cognex), two other medications used to treat Alzheimer's All three belong to a class of drugs called cholinesterase inhibitors
Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice. Sigurdsson EM, Scholtzova H, Mehta PD, Frangione B, Wisniewski T. Department of Neurology, New York University School of Medicine, 550 First Ave., New York, NY 10016, USA.	Am J Pathol 2001 Aug;159(2):439-47 Abstract quote Transgenic mice with brain amyloid-beta (Abeta) plaques immunized with aggregated Abeta1-42 have reduced cerebral amyloid burden. However, the use of Abeta1-42 in humans may not be appropriate because it crosses the blood brain barrier, forms toxic fibrils, and can seed fibril formation. We report that immunization in transgenic APP mice (Tg2576) for 7 months with a soluble nonamyloidogenic, nontoxic Abeta homologous peptide reduced cortical and hippocampal brain amyloid burden by 89% (P = 0.0002) and 81% (P = 0.0001), respectively. Concurrently, brain levels of soluble Abeta1-42 were reduced by 57% (P = 0.0019). Ramified microglia expressing interleukin-1beta associated with the Abeta plaques were absent in the immunized mice indicating reduced inflammation in these animals. These promising findings suggest that immunization with nonamyloidogenic Abeta derivatives represents a potentially safer therapeutic approach to reduce amyloid burden in Alzheimer's disease, instead of using toxic Abeta fibrils.
ANTIOXIDANTS
Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Aggarwal N, Wilson RS, Scherr PA. Rush Institute for Healthy Aging, 1645 W Jackson, Suite 675, Chicago, IL 60612.	JAMA 2002 Jun 26;287(24):3230-7 Related Articles, Books, LinkOut Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Aggarwal N, Wilson RS, Scherr PA. Rush Institute for Healthy Aging, 1645 W Jackson, Suite 675, Chicago, IL 60612. mmorris@rush.edu CONTEXT: Oxidative processes have been suggested as elements in the development of Alzheimer disease (AD), but whether dietary intake of vitamin E and other antioxidant nutrients prevents its development is unknown. OBJECTIVE: To examine whether intake of antioxidant nutrients, vitamin E, vitamin C, and beta carotene is associated with incident AD. DESIGN, SETTING, AND PARTICIPANTS: Prospective study, conducted from 1993 to 2000, of individuals selected in a stratified random sample of community-dwelling residents. The 815 residents 65 years and older were free of AD at baseline and were followed up for a mean of 3.9 years. They completed food frequency questionnaires an average of 1.7 years after baseline. MAIN OUTCOME MEASURE: Incident AD diagnosed in clinical evaluations with standardized criteria. RESULTS: Increasing vitamin E intake from foods was associated with decreased risk of developing AD after adjustment for age, education, sex, race, APOE epsilon4, and length of follow-up. Relative risks (95% confidence intervals [CIs]) from lowest to highest quintiles of intake were 1.00, 0.71 (0.24-2.07), 0.62 (0.26-1.45), 0.71 (0.27-1.88), and 0.30 (0.10-0.92) (P for trend =.05). The protective association of vitamin E was observed only among persons who were APOE epsilon4 negative. Adjustment for other dietary factors reduced the protective association. After adjustment for baseline memory score, the risk was 0.36 (95% CI, 0.11-1.17). Intake of vitamin C, beta carotene, and vitamin E from supplements was not significantly associated with risk of AD. CONCLUSION: This study suggests that vitamin E from food, but not other antioxidants, may be associated with a reduced risk of AD. Unexpectedly, this association was observed only among individuals without the APOE epsilon4 allele.
NSAIDS
Effects of Rofecoxib or Naproxen vs Placebo on Alzheimer Disease Progression: A Randomized Controlled Trial. Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, Farlow MR, Jin S, Thomas RG, Thal LJ. Department of Neurology, Georgetown University Medical Center, Washington, DC.	JAMA. 2003 Jun 4;289(21):2819-26. Abstract quote CONTEXT: Laboratory evidence that inflammatory mechanisms contribute to neuronal injury in Alzheimer disease (AD), along with epidemiological evidence, suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) may favorably influence the course of the disease. OBJECTIVE: To determine whether treatment with a selective cyclooxygenase (COX) -2 inhibitor (rofecoxib) or a traditional nonselective NSAID (naproxen) slows cognitive decline in patients with mild-to-moderate AD. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to study medications. SETTING: Forty ambulatory treatment centers affiliated with the Alzheimer's Disease Cooperative Study consortium. PARTICIPANTS: Participants with mild-to-moderate AD (Mini-Mental State Examination score of 13-26) were recruited from December 1999 to November 2000 using clinic populations, referrals from community physicians, and local advertising. Stable use of cholinesterase inhibitors, estrogen, low-dose aspirin, and vitamin E was allowed. Participants with inflammatory diseases that might respond to the study medications were excluded. Of 474 participants screened, 351 were enrolled. INTERVENTIONS: Once-daily rofecoxib, 25 mg, or twice-daily naproxen sodium, 220 mg, or placebo. MAIN OUTCOME MEASURES: The primary outcome measure was the 1-year change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score. Secondary outcome measures included the Clinical Dementia Rating scale sum-of-boxes, the Neuropsychiatric Inventory, the Quality of Life-AD, and the time to attainment of significant end points (4-point decline from baseline ADAS-Cog score, 1-step worsening on the global Clinical Dementia Rating scale, 15-point decline on the ADCS activities of daily living inventory, institutionalization, or death). RESULTS: The 1-year mean (SD) change in ADAS-Cog scores in participants treated with naproxen (5.8 [8.0]) or rofecoxib (7.6 [7.7]) was not significantly different from the change in participants treated with placebo (5.7 [8.2]). Results of secondary analyses showed no consistent benefit of either treatment. Fatigue, dizziness, and hypertension were more commonly reported in the active drug groups, and more serious adverse events were found in the active treatment group than in the placebo group. CONCLUSION: The results of this study indicate that rofecoxib or low-dose naproxen does not slow cognitive decline in patients with mild-to-moderate AD.

Robbin's Pathologic Basis of Disease. 6th Edition. WB Saunders Company 1999.

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