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Original Contribution |

Association of Low Plasma Aβ42/Aβ40 Ratios With Increased Imminent Risk for Mild Cognitive Impairment and Alzheimer Disease FREE

Neill R. Graff-Radford, MBBCh, FRCP; Julia E. Crook, PhD; John Lucas, PhD; Bradley F. Boeve, MD; David S. Knopman, MD; Robert J. Ivnik, PhD; Glenn E. Smith, PhD; Linda H. Younkin, PhD; Ronald C. Petersen, MD, PhD; Steven G. Younkin, MD, PhD
[+] Author Affiliations

Author Affiliations: Departments of Neurology (Dr Graff-Radford), Biostatistics (Dr Crook), Psychiatry and Psychology (Dr Lucas), and Neuroscience (Drs L. H. Younkin and S. G. Younkin), Mayo Clinic, Jacksonville, Fla; and Departments of Neurology (Drs Boeve, Knopman, and Petersen) and Psychiatry and Psychology (Drs Ivnik and Smith), Mayo Clinic, Rochester, Minn.


Arch Neurol. 2007;64(3):354-362. doi:10.1001/archneur.64.3.354.
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Published online

Background  To develop preventive therapy for Alzheimer disease (AD), it is essential to develop AD-related biomarkers that identify at-risk individuals in the same way that cholesterol levels identify persons at risk for heart disease.

Objective  To determine whether plasma levels of amyloid β protein (Aβ40 and Aβ42) are useful for identifying cognitively normal elderly white subjects at increased risk for mild cognitive impairment (MCI) and AD.

Design  Using well-established sandwich enzyme-linked immunosorbent assays, plasma Aβ40 and Aβ42 levels were analyzed at baseline in a prospective, elderly white cohort followed up for 2 to 12 (median, 3.7) years to detect incident cases of MCI or AD.

Setting  Cognitively normal, community-based white volunteers recruited from primary care settings into the Mayo Rochester Alzheimer Disease Patient Registry.

Patients  We followed up 563 cognitively normal white volunteers (median age, 78 years; 62% female) who had at least 1 follow-up visit after measurement of baseline plasma Aβ levels.

Main Outcome Measures  The primary outcome was time to development of MCI or AD. The secondary outcome was the annualized rate of cognitive change in patients for whom we had 2 Mattis Dementia Rating Scale evaluations 3 to 7 years apart.

Results  During follow-up, 53 subjects developed MCI or AD. Subjects with plasma Aβ42/Aβ40 ratios in the lower quartiles showed significantly greater risk of MCI or AD (P = .04, adjusted for age and apolipoprotein E genotype). Comparison of subjects with plasma Aβ42/Aβ40 ratios in the lowest vs the highest quartile gave a relative risk of 3.1 (95% confidence interval, 1.1-8.3). After adjusting for age and apolipoprotein E genotype, regression analysis using annualized changes in the Dementia Rating Scale scores as an outcome variable showed that participants with lower Aβ42/Aβ40 ratios had greater cognitive decline (P = .02).

Conclusion  The plasma Aβ42/Aβ40 ratio may be a useful premorbid biomarker for identifying cognitively normal elderly white subjects who are at increased risk for developing MCI or AD.

Figures in this Article

There is a growing consensus that the best way to manage Alzheimer disease (AD) will ultimately be through preventive therapy similar to that used for atherosclerotic heart disease. To facilitate preventive therapy, it is important to develop AD-related biomarkers that can be used to identify at-risk individuals in the same way that cholesterol levels are used to identify those at risk for atherosclerotic heart disease. In 1998, the Consensus Report of the Working Group on Molecular and Biochemical Markers of Alzheimer Disease1 proposed that an ideal diagnostic marker for AD should be reliable, able to detect a fundamental feature of AD neuropathology, and validated through confirmed cases. In addition, it should be noninvasive, simple to perform, and inexpensive. These criteria apply equally well to premorbid and diagnostic biomarkers. In this study, we evaluated plasma amyloid β protein (Aβ40 and Aβ42) and the Aβ42/Aβ40 ratio as premorbid biomarkers for AD and the amnestic type of mild cognitive impairment (MCI),2 which usually precedes AD.

The deposition of Aβ in senile plaques is a pathological hallmark of AD. Measurement of plasma Aβ40 and Aβ42 levels is noninvasive, and it could be developed into a test that is as simple to perform and inexpensive as the test for high- and low-density lipoprotein levels. Thus, plasma Aβ40, Aβ42, and the Aβ42/Aβ40 ratio could be highly useful premorbid biomarkers if they are reliable predictors of MCI and AD.

The amyloid β protein is a secreted peptide, normally present in plasma and cerebrospinal fluid (CSF), that is derived from a large precursor protein through the sequential action of 2 proteases referred to as β and γ secretase.3 Most secreted Aβ has 40 amino acids (Aβ40), but a small percentage has 42 (Aβ42).3 In all patients with AD, Aβ42 aggregates and deposits in the brain, forming senile plaques that are one of the pathological hallmarks of AD.4 Studies of autopsied brains have shown that the Aβ deposited in AD has a ragged amino terminus and that, in approximately one third of patients, Aβ42 is virtually the only form deposited.4 In another third, Aβ42 is the major form deposited and, in the remaining third, large amounts of Aβ40 and Aβ42 are deposited.4

The level of Aβ42 in CSF is significantly reduced both in patients with AD and in those with MCI, which precedes AD.5 In the Tg2576 mouse model of AD, the CSF Aβ level also declines as Aβ is deposited in the brain.6 Importantly, plasma Aβ levels decline in parallel.6

Other observations suggest that, in many patients with AD, deposition of Aβ42 may be preceded and fostered by an elevated level of Aβ that can be detected in plasma. Patients with trisomy 21, who invariably develop AD pathology if they live past 40 years of age, have higher plasma Aβ40 and Aβ42 levels compared with controls from birth.7,8 Although Aβ40 and Aβ42 levels are elevated in trisomy 21, the study of trisomy 21 brains obtained at autopsy has shown that Aβ42 is deposited before Aβ40. It is well established that virtually all of the genetic mutations that cause early-onset familial AD increase the Aβ42 level in a way that is detectable in plasma.9 More recently, we10 and others11 have shown that plasma Aβ40 and Aβ42 levels increase with aging, one of the most important risk factors for AD. Finally, Ertekin-Taner et al12 have shown that plasma Aβ40 and Aβ42 levels are elevated in asymptomatic first-degree relatives of patients with AD, who are known to be at increased risk for AD.

These summarized results indicate that Aβ42 levels are reduced in the CSF of patients with MCI or AD in association with the selective deposition of Aβ42 that occurs in the brain. They suggest that the plasma Aβ42 level and Aβ42/Aβ40 ratio may decline in parallel, but in many at-risk individuals plasma Aβ40 and Aβ42 levels appear to be elevated initially; thus, the plasma Aβ42 level may often decline into the normal range as Aβ42 deposition commences. This makes the Aβ42/Aβ40 ratio a potential biomarker for selective Aβ42 deposition. The results of the longitudinal study presented herein are, to our knowledge, the first to indicate that the plasma Aβ42/Aβ40 ratio may be useful for identifying elderly white subjects who are at imminent risk for MCI or AD.

PARTICIPANT SELECTION

This study was performed under the supervision of the Mayo Institutional Review Board and all participants signed informed consent.

Participants were 563 cognitively normal older adults forming a complete subset of those who entered the Mayo Clinic Alzheimer Disease Patient Registry (ADPR) as normal controls from 1992 through 2003 and had at least 2 stored plasma specimens. For purposes of this and all ADPR studies, cognitively normal adults are defined as community-dwelling, independently functioning individuals who were examined by their primary care physician and met the following selection criteria:

  1. No complaints of memory or other cognitive difficulties during the history taking or systems review components of their medical examination, and no medical examination findings suggestive of cognitive compromise.

  2. No active neurologic or psychiatric conditions with the potential to affect cognition adversely.

  3. No use of psychoactive medication in amounts sufficient to affect cognition.

  4. An informant noted that the person's memory was normal.

Individuals with histories of medical conditions or disorders that may affect cognition (eg, head injury) were included only if the condition was no longer active and there was no evidence of persistent or residual cognitive impairment. Individuals with current, chronic medical conditions (eg, hypertension or diabetes) were included if their physician judged their condition to be well controlled and not affecting cognition.

BASELINE EVALUATION

All participants underwent baseline neurologic and neuropsychological evaluations. In addition, a study nurse collected collateral information, including family history of dementia, current medications, the Clinical Dementia Rating,13 and the Neuropsychiatric Inventory14 from an informant. Activities of daily living were evaluated using parts A and B of the Record of Independent Living.15 Data from informants were available for 98% of the study participants. Family members provided data 84% of the time and close friends provided information 14% of the time. When an informant was not available, information was solicited directly from the participant.

After these data were collected, a neurologist reviewed the Clinical Dementia Rating score with the participant and informant and performed a neurologic examination, including the Kokmen Short Test of Mental Status,16 Hachinski Ischemic Index,17 and Unified Parkinson's Disease Rating Scale.18 An experienced psychometrist then administered a baseline battery of neuropsychological tests, including the Dementia Rating Scale (DRS),19 Auditory Verbal Learning Test,20 Wechsler Memory Scale–Revised,21 and Wechsler Adult Intelligence Scale–Revised.22

FOLLOW-UP EVALUATIONS

Study participants were contacted annually for reevaluation. Medication lists and information regarding family history of dementia were updated at each follow-up visit. In addition, the Clinical Dementia Rating, Record of Independent Living, Neuropsychiatric Inventory, Hachinski Ischemic Index, Unified Parkinson's Disease Rating Scale, Kokmen Short Test of Mental Status, and neuropsychological test battery were repeated.

CONSENSUS DIAGNOSIS

All baseline and follow-up examinations were reviewed at a weekly consensus conference, staffed by Mayo Alzheimer's Disease Research Center neurologists, neuropsychologists, nurses, psychometrists, a geriatrician, and a social worker. At baseline, entry criteria were reviewed and a Clinical Dementia Rating score of 0 was confirmed for all individuals enrolled in the ADPR as normal. Neuropsychological data were used to make the consensus diagnosis. Persons not meeting these criteria were assigned a clinical diagnosis and offered follow-up through alternate study mechanisms, if appropriate.

At the annual follow-up, all diagnostic information, including neuropsychological data, was reviewed at a consensus conference. Data were compared with those of baseline studies to evaluate progression to MCI or dementia. Diagnoses of amnestic and nonamnestic MCI were determined using Mayo criteria.23 Standard published criteria were used to diagnose possible and probable AD.24 Participants with abnormal clinical findings on follow-up but who did not meet the established criteria for MCI or dementia were coded as having cognitive impairment of undetermined origin. In the follow-up of this series, we have reported that more than 85% of amnestic MCI cases convert to AD by 7 years.25 For this reason and because of limited numbers of patients converting to AD, we combined our end point as incident cases of amnestic MCI and AD (MCI/AD).

For inclusion in the analysis, we required that participants be originally recruited as cognitively normal, have at least 12 months of follow-up beyond the first sample, and be older than 55 years. Table 1 shows the characteristics of the 563 participants who met these criteria. Median follow-up for this study was 3.7 (25%-75% range, 2.6-5.9) years. Within 15 months of the abstraction for this study, 444 of these 563 ADPR participants had follow-up visits and were still active. Six participants had only 1 follow-up visit, 171 had a total of 3 visits, 155 had 4 visits, 69 had 5 visits, and the remaining 162 had 6 or more visits. Fifty-three participants (9.4%) were diagnosed as having MCI/AD during their follow-up. Of the 53 converters, 36 developed MCI, and 7 of these went on to develop AD (5 probable and 2 possible). The other 17 developed AD (12 probable and 5 possible) without being observed with MCI. Median age at the first plasma sample was 78 (25%-75% range, 73-83) years, and median age of onset of MCI/AD was 88 (25%-75% range, 85-92) years.

Table Graphic Jump LocationTable 1. Characteristics of the 563 Cognitively Normal Patients at Baseline

Recent data indicate that medications and supplements may influence Aβ levels.26 We elected not to adjust for this potential confounder because the list of medications that may affect Aβ is evolving and uncertain and because the effect of suggested Aβ modifiers in the doses normally given to elderly subjects has yet to be firmly established in large follow-up studies.

COGNITIVE CHANGE AND PLASMA Aβ LEVELS

To evaluate the relationship of cognitive change to plasma Aβ levels, we identified a subgroup of individuals who had 2 DRS evaluations approximately 5 years apart and a plasma sample at the time of the first evaluation. They also had to be cognitively normal at the first time point. A window of 5 (±2) years was used for the time between DRS evaluations, and a window of ±6 months was used for the time between the initial visit and the date the plasma sample was obtained. The cohort who met these criteria consisted of 379 persons, of whom 237 (63%) were female, with a median age of 77 years and a median education of 13 years.

METHOD OF MEASURING PLASMA Aβ40 AND Aβ42 LEVELS

At each visit, nonfasting patients had blood drawn into an EDTA tube. The plasma was spun off, divided into 1-mL aliquots, and stored at −70°C. One aliquot was used to measure the plasma Aβ levels. Plasma Aβ measures were made using an enzyme-linked immunosorbent assay method with the well-characterized antibodies BAN-50/BA27 specific for Aβ40 and BAN-50/BC05 specific for Aβ42.9Figure 1 shows the distributions of raw plasma Aβ levels.

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Figure 1.

Histograms of distributions of raw plasma amyloid β protein (Aβ) measures in all 563 patients at baseline. Vertical dotted lines show locations of quartiles.

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STATISTICAL METHODS

The Kaplan-Meier method was used to estimate the distribution of time to development of MCI/AD, with the time of the first plasma sample considered as the start of follow-up. These times were censored at the date of the last follow-up for patients who never developed MCI/AD. Cox proportional hazards models were used to investigate associations with Aβ measures. Because of the extremely skewed distributions of the Aβ measures and a number of outliers (Figure 1), in this analysis the Aβ42 and Aβ40 levels and Aβ42/Aβ40 ratio were included in models in a number of different ways so that sensitivity of results could be explored. The primary approach was to include each Aβ measure as a numerical variable defined by the quartiles of the distribution. Quartiles (labeled as Q1-Q4) were also included as categorical variables to enable estimation of hazard ratios relative to the highest quartile and to aid in exploring whether a linear association was reasonable. Other approaches were to include each Aβ measure as a continuous variable on the logarithm scale and as a binary category variable defined by the median. Sensitivity of results to the removal of the outlying Aβ measures (the upper and lower 2%) was considered in the continuous variable models. Age, sex, presence of a 3/4 or 4/4 genotype of apolipoprotein E (APOE), years of education, age-adjusted DRS score, and family history of dementia were considered to be potential confounding variables and, of these, age and APOE4 allele showed evidence of an association with the Aβ40 level, Aβ42/Aβ40 ratio, as well as with time to MCI/AD at the 0.20 significance level (Table 2 and Table 3). We designated these to be likely confounding variables and adjusted for them in the primary analyses addressing the association of Aβ measures with time to MCI/AD. No adjustments were made for multiple testing in these exploratory analyses.

Table Graphic Jump LocationTable 2. Patient Characteristics by Plasma Aβ Measure Quartiles
Table Graphic Jump LocationTable 3. Associations of Time to MCI or AD With Patient Characteristics

Further regression models were used to explore the relationship between Aβ measures and change in cognition during a subsequent period of approximately 5 years in a subset of 379 participants who were administered the DRS within 6 months of an Aβ measure. The total DRS raw score was converted to an age-adjusted scaled score on the basis of data from the Mayo Older American Normative Study. Because follow-up intervals varied, annualized rates of cognitive change were used as the outcome variable in the least-squares regression analyses that were conducted similarly to the time-to-conversion analyses.

Fifty-three of the 563 subjects developed MCI/AD. The estimated cumulative incidence in this cohort of patients (Figure 2) with a median age of 78 years at the start of follow-up was 5% at 4 years, with 95% confidence interval (CI) ranging from 3% to 8%. It reached 11% (95% CI, 7%-14%) at 6 years, 18% (95% CI, 12%-24%) at 8 years, and 30% (95% CI, 19%-39%) at 10 years of follow-up. Advancing age and APOE genotype, 2 well-established risk factors for AD, showed evidence of association with incidence of MCI/AD (Table 3), whereas family history did not.

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Figure 2.

Incidence of mild cognitive impairment (MCI) or Alzheimer disease (AD). Dashed lines represent 95% confidence intervals for the estimated proportion with MCI or AD at each time point. The numbers of patients remaining at risk of developing MCI or AD at each time point are shown below the graph. For each time point, this is the number of individuals who have been followed up for that length of time and remain cognitively normal.

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The plasma Aβ42/Aβ40 ratio showed evidence of association with conversion to MCI/AD (Table 4), but the Aβ42 and Aβ40 levels did not (Table 4). The risk of MCI/AD for patients with an Aβ42/Aβ40 ratio in the lowest quartile was estimated to be 3 times the risk for subjects with a ratio in the highest quartile (P = .01), and this association persisted (P = .04) after adjusting for age and APOE genotype. The relationship between the Aβ42/Aβ40 ratio and cumulative incidence of MCI/AD is shown graphically in Figure 3. Subjects whose Aβ42/Aβ40 ratio was in the lowest quartile (Q1, <0.05) reached a 10% incidence by 3 years, followed by those in Q2 who took approximately 5 years, and those in Q3 and Q4 who took approximately 8 years to reach 10% cumulative incidence. This pattern was suggestive of a deviation from the proportional hazards assumption of our models, but formal significance tests indicated no significant deviation.

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Figure 3.

Proportion of individuals who developed mild cognitive impairment (MCI) or Alzheimer disease (AD) according to quartiles of the ratio of amyloid β protein 42/40 (Aβ42/Aβ40).

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Table Graphic Jump LocationTable 4. Time to MCI or AD and Aβ Measures

Figure 4 shows the cumulative incidence of MCI/AD stratified according to whether the Aβ42/Aβ40 ratio was above or below the median separately for patients with the APOE 3/3 and 3/4 genotypes. Figure 5 similarly groups patients by the Aβ42/Aβ40 ratio and age. Figure 6 shows the estimated proportions of individuals with MCI/AD after 5 years of follow-up depending on the combined effects of age (<80 or ≥80 years), Aβ42/Aβ40 ratio (above or below the median), and specific APOE genotype (3/3 or 3/4). Among older subjects with the 3/4 genotype, the estimated incidence at 5 years was 32% (95% CI, 9%-50%) for those with an Aβ42/Aβ40 ratio below the median, compared with only 6% (95% CI, 0%-16%) for those with a ratio above the median. For older subjects with the 3/3 genotype, the incidences were 17% (95% CI, 6%-26%) and 7% (95% CI, 0%-15%) for those with ratios below and above the median, respectively. Among younger individuals with the 3/4 genotype, the 5-year incidence was 10% (95% CI, 0%-23%) for those with a low Aβ42/Aβ40 ratio, compared with 3% (95% CI, 0%-9%) for those with a higher ratio. In the lowest risk group according to age and APOE genotype (<80 years with the 3/3 genotype), the estimated incidence was only 2%, regardless of whether the Aβ42/Aβ40 ratio was below or above the median (95% CIs, 0%-7% and 0%-6%, respectively).

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Figure 4.

Probability of mild cognitive impairment (MCI) or Alzheimer disease (AD) according to the ratio of amyloid β protein 42/40 (Aβ42/Aβ40) and the presence of a 3/4 or 4/4 genotype of apolipoprotein E. After 5 years of follow-up, among patients with the 3/4 genotype, 21% of subjects with a low (below the median) Aβ42/Aβ40 ratio had developed MCI/AD, in contrast to only 4% of those with a high (above the median) ratio. The median Aβ42/Aβ40 ratio was 0.064.

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Figure 5.

Probability of mild cognitive impairment (MCI) or Alzheimer disease (AD) according to the ratio of amyloid β protein 42/40 (Aβ42/Aβ40) and age. Among older subjects (older than 80 years), 20% of patients with a low (below the median) Aβ42/Aβ40 ratio had developed MCI/AD by 5 years, in contrast to less than 5% for older subjects with a high (above the median) ratio.

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Figure 6.

Five-year incidence of mild cognitive impairment (MCI) or Alzheimer disease (AD) according to the ratio of amyloid β protein 42/40 (Aβ42/Aβ40), age, and apolipoprotein E (APOE) genotype. The 95% confidence intervals are included (limit lines). Results are shown only for the 3/3 and 3/4 genotypes because incidence was too low among patients with other genotypes (only 6 conversions).

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The regression analysis using changes in DRS scores as the outcome variable in a subset of patients resulted in confirmatory findings. After adjustment for age and APOE genotype, the Aβ42/Aβ40 ratio showed similar levels of evidence of association with decline in cognition, with lower ratios being associated with greater declines (Table 5).

Table Graphic Jump LocationTable 5. Association of Aβ42/Aβ40 Ratio and Change in DRS Total MOANS Score

Our findings indicate that cognitively normal elderly white subjects with low Aβ42/Aβ40 ratios may be at increased risk for MCI/AD. This association is best explained by postulating that the time course of cerebral Aβ aggregation and deposition is extended, typically occurring over a period of 10 to 15 years before MCI/AD develops in the elderly white population that we studied. Amyloid β42 deposits selectively in the AD brain,4 and it is well established that the CSF Aβ42 level is decreased in subjects with MCI or AD. In the Tg2576 model of AD, the plasma Aβ levels decline in parallel with the CSF Aβ level as Aβ deposits in the brain. We postulate, therefore, that the CSF and plasma Aβ42 levels decline in parallel as Aβ42 deposits selectively in the human AD brain. Because Aβ42 aggregation and deposition precede MCI/AD, most subjects who develop MCI/AD have a low Aβ42/Aβ40 ratio several years before MCI/AD can be diagnosed. Thus, we postulate that the plasma Aβ42/Aβ40 ratio is not a trait variable like the APOE4 allele or family history. It is rather a state variable that reflects the extent to which there has been selective aggregation and deposition of Aβ42 in the brain.

It is well established that the risk for AD increases with aging and that it increases in first-degree relatives up to the age of approximately 80 years. Both of these factors are associated with increases in plasma Aβ40 and Aβ42 levels. If the time course of aggregation and deposition is extended as our data suggest, then elderly white subjects with elevated Aβ levels will be at increased risk for MCI/AD but not at increased immediate risk that could be detected in a 5-year period. In subjects who begin with elevated Aβ40 and Aβ42 levels, the plasma Aβ42 level may decline into the normal range as selective Aβ42 deposition occurs and the Aβ42/Aβ40 ratio falls into the lowest quartile. This could explain why imminent MCI/AD is predicted better by a low Aβ42/Aβ40 ratio than by a low Aβ42 level alone.

Two studies27,28 from North Manhattan, NY, have been reported in which the plasma Aβ level was analyzed as a premorbid biomarker for AD. In both studies, an elevated Aβ42 level was associated with an increased risk of conversion to AD. There were, however, important differences between those studies and the one we report herein. The population assessed in the studies reported from North Manhattan differed from our population in 2 important ways: the incidence rate was much higher (16% at 5 years for AD vs 9% at 5 years for MCI/AD in this study), despite a slightly lower mean age at baseline (76 vs 78 years), and the population was mixed (one third consisted of African American subjects; one third, Caribbean Hispanic first-generation immigrants; and one third, white subjects) with 16.8% of the African American, 19.7% of the Caribbean Hispanic, and 7.6% of the white subjects developing AD in those studies. The African American and Caribbean Hispanic subjects not only had a higher incident rate than the white population, but also differed in important ways such as having different APOE4 frequencies. The apparent conflict between our results and those reported by Mayeux et al27,28 can be resolved by postulating that elevated Aβ42 levels cause AD relatively quickly in the North Manhattan population but more slowly in the our elderly white population. In the North Manhattan population, the relatively short time from the elevation of the Aβ42 level to the onset of AD would make an elevated Aβ42 level a good predictor for imminent AD. If the time from the Aβ42 level elevation to onset of MCI/AD was greater in our white population, then the plasma Aβ42 level would decline into the normal range in the premorbid period as Aβ42 deposits selectively in the brain and the Aβ42/Aβ40 ratio would fall to low levels, making the Aβ42/Aβ40 ratio a better predictor of imminent MCI/AD in this population.

The relative risk of AD in first-degree relatives of subjects with AD declines with aging, as does the relative risk in those with an APOE4 allele. In our series, which was composed of many subjects older than 80 years, family history (defined as being a first-degree relative of a person with AD) showed no significant association with progression to MCI/AD. After correcting for age and APOE genotype, the relative risk for family history was only 1.1, with a 95% CI of 0.7 to 2.0 and a P value of .67. After correcting for age, the relative risk associated with a higher-risk APOE genotype (3/4 or 4/4) was 2.1, with a 95% CI of 1.2 to 3.7 and a P value of .01.

The estimated relative risk of 3.1 that we obtained for the Aβ42/Aβ40 ratio in our exploratory evaluation of Aβ levels in an elderly white population suggests that, in this population, the Aβ42/Aβ40 ratio may be as useful as APOE4 and more useful than family history as a premorbid biomarker for identifying those at imminent risk for MCI/AD. The results obtained when we assessed the combined effect of the Aβ42/Aβ40 ratio and aging were particularly striking. In those older than 80 years whose Aβ42/Aβ40 ratio was below the median, the 5-year cumulative incidence of MCI/AD was approximately 20%. In all other subjects, it was approximately 5%. If these findings are confirmed in additional large longitudinal studies, the plasma Aβ42/Aβ40 ratio could become an important biomarker for developing and implementing a preventive approach to AD therapy in elderly white subjects.

—————————————————————

Since the manuscript was submitted, van Oijen et al29 published a study analyzing plasma Aβ (Aβ42, Aβ40, and the Aβ40/Aβ42 ratio) in a large case-cohort study embedded in the prospective, population-based Rotterdam Study. Their results are similar to those reported in our study.

Correspondence: Neill R. Graff-Radford, MBBCh, FRCP, Department of Neurology, or Steven G. Younkin, MD, PhD, Department of Neuroscience, Mayo College of Medicine, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224 (graffradford.neill@mayo.edu or younkin.steven@mayo.edu).

Accepted for Publication: July 6, 2006.

Author Contributions: Drs Graff-Radford and S. G. Younkin had full access to the data and take responsibility for the integrity of the data and accuracy of the data analysis. Study concept and design: Graff-Radford, L. H. Younkin, and S. G. Younkin. Acquisition of data: Lucas, Boeve, Knopman, Ivnik, L. H. Younkin, and S. G. Younkin. Analysis and interpretation of data: Graff-Radford, Crook, Ivnik, Smith, Petersen, and S. G. Younkin. Drafting of the manuscript: Graff-Radford, Crook, L. H. Younkin, Petersen, and S. G. Younkin. Critical revision of the manuscript for important intellectual content: Graff-Radford, Crook, Lucas, Boeve, Knopman, Ivnik, Smith, Petersen, and S. G. Younkin. Statistical analysis: Crook, Smith, and S. G. Younkin. Obtained funding: Graff-Radford, Petersen, and S. G. Younkin. Administrative, technical, and material support: Lucas, Boeve, Smith, L. H. Younkin, Petersen, and S. G. Younkin. Study supervision: Graff-Radford and S. G. Younkin.

Financial Disclosure: Drs Graff-Radford, Crook, Lucas, L. H. Younkin, and S. G. Younkin have been included as inventors in a patent application filed by the Mayo Clinic on the Aβ42/Aβ40 ratio as a predictive test for MCI and AD.

Funding/Support: This study was supported by grants R01 AG06656, P50 AG16574, and U01 AG06786 from the National Institute on Aging, and by the Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program.

Role of the Sponsors: The funding agencies had no role in the design or conduct of the study; the collection, management, and analysis of data; or the preparation, review, and approval of the manuscript.

Acknowledgment: We thank the following research assistants, of Jacksonville, Fla, for their assistance: Francine Parfitt, MA, Josie Pagdanganan, Jennifer Adamson, and Michael Heckman, MS.

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Morris  JC The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993;432412- 2414
PubMed Link to Article
Cummings  JLMega  MGray  KRosenberg-Thompson  SCarusi  DGornbein  J The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia. Neurology 1994;442308- 2314
PubMed Link to Article
Weintraub  S The Record of Independent Living: an informant-completed measure of activities of daily living and behavior in elderly patients with cognitive impairment. Am J Alzheimer Care Relat Disord 1986;735- 39
Link to Article
Kokmen  ESmith  GPetersen  RTangalos  EIvnik  R The short test of mental status: correlations with standardized psychometric testing. Arch Neurol 1991;48725- 728
PubMed Link to Article
Hachinski  VCLassen  NAMarshall  J Multi-infarct dementia: a cause of mental deterioration in the elderly. Lancet 1974;2 ((7874)) 207- 210
PubMed Link to Article
Fahn  SElton  RMot  UDC Unified Parkinson's Disease Rating Scale.  In: Fahn  S, Marsden  C, Calne  D, Golstein  M, eds. Recent Developments in Parkinson's Disease. New York, NY: MacMillan Publishing Co Inc; 1987
Mattis  S Dementia Rating Scale.  Odessa, Fla: Psychological Assessment Resources; 1983
Rey  A L’examen psychologique dans les cas d’encephalopathie traumatique. Arch Psychol 1941;28286- 340
Wechsler  D Wechsler Memory Scale–Revised.  New York, NY: Psychological Corporation; 1987
Wechsler  D Wechsler Adult Intelligence Scale–Revised.  New York, NY: Psychological Corporation; 1981
Petersen  RCSmith  GEWaring  SCIvnik  RJTangalos  EGKokmen  E Mild cognitive impairment. Arch Neurol 1999;56303- 308
PubMed Link to Article
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  E 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. Neurology 1984;34939- 944
PubMed Link to Article
Petersen  RCDoody  RKurz  A Current concepts in mild cognitive impairment. Arch Neurol 2001;581985- 1992
PubMed Link to Article
Blasko  IKemmler  GKrampla  W Plasma amyloid beta protein 42 in non-demented persons aged 75 years: effects of concomitant medication and medial temporal lobe atrophy. Neurobiol Aging 2005;261135- 1143
PubMed Link to Article
Mayeux  RTang  M-XJacobs  D Plasma amyloid β-peptide 1-42 and incipient Alzheimer's disease. Ann Neurol 1999;46412- 416
PubMed Link to Article
Mayeux  RHonig  LSMTang  MXP Plasma Aβ40 and Aβ42 and Alzheimer's disease: relation to age, mortality, and risk. Neurology 2003;611185- 1190
PubMed Link to Article
van Oijen  MHofman  ASoares  HDKoudstaal  PJBreteler  MM Plasma Aβ1-40 and Aβ1-42 and the risk of dementia: a prospective case-cohort study. Lancet Neurol 2006;5655- 660
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Histograms of distributions of raw plasma amyloid β protein (Aβ) measures in all 563 patients at baseline. Vertical dotted lines show locations of quartiles.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Incidence of mild cognitive impairment (MCI) or Alzheimer disease (AD). Dashed lines represent 95% confidence intervals for the estimated proportion with MCI or AD at each time point. The numbers of patients remaining at risk of developing MCI or AD at each time point are shown below the graph. For each time point, this is the number of individuals who have been followed up for that length of time and remain cognitively normal.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Proportion of individuals who developed mild cognitive impairment (MCI) or Alzheimer disease (AD) according to quartiles of the ratio of amyloid β protein 42/40 (Aβ42/Aβ40).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Probability of mild cognitive impairment (MCI) or Alzheimer disease (AD) according to the ratio of amyloid β protein 42/40 (Aβ42/Aβ40) and the presence of a 3/4 or 4/4 genotype of apolipoprotein E. After 5 years of follow-up, among patients with the 3/4 genotype, 21% of subjects with a low (below the median) Aβ42/Aβ40 ratio had developed MCI/AD, in contrast to only 4% of those with a high (above the median) ratio. The median Aβ42/Aβ40 ratio was 0.064.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

Probability of mild cognitive impairment (MCI) or Alzheimer disease (AD) according to the ratio of amyloid β protein 42/40 (Aβ42/Aβ40) and age. Among older subjects (older than 80 years), 20% of patients with a low (below the median) Aβ42/Aβ40 ratio had developed MCI/AD by 5 years, in contrast to less than 5% for older subjects with a high (above the median) ratio.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 6.

Five-year incidence of mild cognitive impairment (MCI) or Alzheimer disease (AD) according to the ratio of amyloid β protein 42/40 (Aβ42/Aβ40), age, and apolipoprotein E (APOE) genotype. The 95% confidence intervals are included (limit lines). Results are shown only for the 3/3 and 3/4 genotypes because incidence was too low among patients with other genotypes (only 6 conversions).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Characteristics of the 563 Cognitively Normal Patients at Baseline
Table Graphic Jump LocationTable 2. Patient Characteristics by Plasma Aβ Measure Quartiles
Table Graphic Jump LocationTable 3. Associations of Time to MCI or AD With Patient Characteristics
Table Graphic Jump LocationTable 4. Time to MCI or AD and Aβ Measures
Table Graphic Jump LocationTable 5. Association of Aβ42/Aβ40 Ratio and Change in DRS Total MOANS Score

References

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PubMed
Petersen  RC Mild cognitive impairment as a diagnostic entity. J Intern Med 2004;256183- 194
PubMed Link to Article
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Gravina  SAHo  LEckman  CB Amyloid beta protein (Aβ) in Alzheimer's disease brain: biochemical and immunocytochemical analysis with antibodies specific for forms ending at Aβ40 or Aβ42(43). J Biol Chem 1995;2707013- 7016
PubMed Link to Article
Andreasen  NMinthon  LDavidsson  P Evaluation of CSF-tau and CSF-Aβ42 as diagnostic markers for Alzheimer disease in clinical practice. Arch Neurol 2001;58373- 379
PubMed Link to Article
Kawarabayashi  TYounkin  LHSaido  TCShoji  MAshe  KHYounkin  SG Age-dependent changes in brain, CSF, and plasma amyloid β protein in the Tg2576 transgenic mouse model of Alzheimer's disease. J Neurosci 2001;21372- 381
PubMed
Graff-Radford  NEckman  CO’Brien  PYounkin  S Plasma amyloid β protein (Aβ) in Down's syndrome (DS): implications for Alzheimer's disease. Neurology 1997;47A378
Schupf  NPatel  BSilverman  W Elevated plasma amyloid β-peptide 1–42 and onset of dementia in adults with Down syndrome. Neurosci Lett 2001;301199- 203
PubMed Link to Article
Scheuner  DEckman  CJensen  M Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med 1996;2864- 870
PubMed Link to Article
Graff-Radford  NEckman  CYounkin  S Amyloid β protein in plasma of Alzheimer's disease patients and controls. Neurology 1996;46A161
Fukumoto  HTennis  MLocascio  JJHyman  BTGrowdon  JHIrizarry  MC Age but not diagnosis is the main predictor of plasma amyloid β-protein levels. Arch Neurol 2003;60958- 964
PubMed Link to Article
Ertekin-Taner  NGraff-Radford  NYounkin  LH Heritability of plasma amyloid beta in typical late-onset Alzheimer's disease pedigrees. Genet Epidemiol 2001;2119- 30
PubMed Link to Article
Morris  JC The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993;432412- 2414
PubMed Link to Article
Cummings  JLMega  MGray  KRosenberg-Thompson  SCarusi  DGornbein  J The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia. Neurology 1994;442308- 2314
PubMed Link to Article
Weintraub  S The Record of Independent Living: an informant-completed measure of activities of daily living and behavior in elderly patients with cognitive impairment. Am J Alzheimer Care Relat Disord 1986;735- 39
Link to Article
Kokmen  ESmith  GPetersen  RTangalos  EIvnik  R The short test of mental status: correlations with standardized psychometric testing. Arch Neurol 1991;48725- 728
PubMed Link to Article
Hachinski  VCLassen  NAMarshall  J Multi-infarct dementia: a cause of mental deterioration in the elderly. Lancet 1974;2 ((7874)) 207- 210
PubMed Link to Article
Fahn  SElton  RMot  UDC Unified Parkinson's Disease Rating Scale.  In: Fahn  S, Marsden  C, Calne  D, Golstein  M, eds. Recent Developments in Parkinson's Disease. New York, NY: MacMillan Publishing Co Inc; 1987
Mattis  S Dementia Rating Scale.  Odessa, Fla: Psychological Assessment Resources; 1983
Rey  A L’examen psychologique dans les cas d’encephalopathie traumatique. Arch Psychol 1941;28286- 340
Wechsler  D Wechsler Memory Scale–Revised.  New York, NY: Psychological Corporation; 1987
Wechsler  D Wechsler Adult Intelligence Scale–Revised.  New York, NY: Psychological Corporation; 1981
Petersen  RCSmith  GEWaring  SCIvnik  RJTangalos  EGKokmen  E Mild cognitive impairment. Arch Neurol 1999;56303- 308
PubMed Link to Article
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  E 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. Neurology 1984;34939- 944
PubMed Link to Article
Petersen  RCDoody  RKurz  A Current concepts in mild cognitive impairment. Arch Neurol 2001;581985- 1992
PubMed Link to Article
Blasko  IKemmler  GKrampla  W Plasma amyloid beta protein 42 in non-demented persons aged 75 years: effects of concomitant medication and medial temporal lobe atrophy. Neurobiol Aging 2005;261135- 1143
PubMed Link to Article
Mayeux  RTang  M-XJacobs  D Plasma amyloid β-peptide 1-42 and incipient Alzheimer's disease. Ann Neurol 1999;46412- 416
PubMed Link to Article
Mayeux  RHonig  LSMTang  MXP Plasma Aβ40 and Aβ42 and Alzheimer's disease: relation to age, mortality, and risk. Neurology 2003;611185- 1190
PubMed Link to Article
van Oijen  MHofman  ASoares  HDKoudstaal  PJBreteler  MM Plasma Aβ1-40 and Aβ1-42 and the risk of dementia: a prospective case-cohort study. Lancet Neurol 2006;5655- 660
PubMed Link to Article

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