Table 68APOE genotype and risk of cognitive decline

StudySample (n)FollowupExposureCase definitionConfounding adjustmentResults
Wilson et al., 2002366Community cohort (669)2 to 8 yearsAPOE genotypeChange on index of combined cognitive tests in separate cognitive domains

Tests listed in table legends
e2 semantic memory decline slower than e3/3
e4 decline > e3 in semantic memory and perceptual speed, not working memory or visuospatial ability
Bretsky et al., 2003367Community cohort (965)7 yearsAPOE genotypeDecline of ≥ 1 SD on individual tests and summary scores as listed in table legendAge
Risk of decline of e4 carriers on global cognitive score: OR 2.0 (95% CI 1.1 to 3.6)
Blair et al., 2005368Community cohort (1693 African-Americans and 6202 Caucasians used in analysis)6 yearsAPOE genotypeDecline on DWR, DSST, and COWA, categorized by quintilesAge
Baseline cognition
Cigarette smoking
Comparing quintile of greatest change to all other quintiles, risk for decline in AA, e4/4 compared to e3/3:
DWR OR 1.72 (95% CI 0.97 to 3.06)
DSST OR 1.86 (1.06 to 3.27)
Risk for decline in Caucasians.
Compared to e3/3 genotype
e2 group DWR OR 0.78 (95% CI 0.61 to 0.98);
e4 group (e3/4 or e2/4) DWR OR 1.19 (1.01 to 1.41)
e4/4 DWR OR1.53 (0.95 to 2.45)

DSST: e4/4 compared to e3/3: OR 2.02 (1.31 to 3.12)
Christensen et al., 2008331Community cohort (2021)4 yearsAPOE genotypeDecline on:
Reaction time
Digits backwards
Educational level
Premorbid intelligence
History of stroke
Current HTN
APOE e4 associated with greater decline on MMSE only (F = 3.55; p = 0.029), but no difference on other tests.
Haan et al., 1999274Community cohort (3622)7 yearsAPOE genotype
Annual rate of change on 3MS and DSSTAge
Incident stroke
Higher annual rate of decline on DSST in APOE e4 positive versus e4 negative individuals (p < 0.0001).

No difference on 3MS

Interaction between APOE e4 and diabetes (p < 0.001) on 3MS:

APOE e4+ and diabetes+: −0.39
APOE e4+ and diabetes−: −0.70
APOE e4− and diabetes+: −0.46
APOE e4− and diabetes−: −0.23
Knopman et al., 2009260Community cohort (1130)Median 14 yearsAPOE genotypeDSST
Educational level
Vascular factors
Risk factor x time interaction
Difference in average baseline cognitive test scores (P value) – APOE genotype:
DSST: 1.06 (0.03)
DWR: 0.17 (0.49)
WF: 0.59 (0.405)

Difference in annual rate of change (P value) – APOE e4 genotype:
DSST: −0.10 (0.004)
DWR: −0.03 (< 0.001)
WF: −0.04 (NS)
Tervo et al., 2004267Community cohort (747)3.26 ± 0.7 yearsAPOE genotypeClinical Dementia Rating (CDR): MCI diagnosed if score of 0.5 and if subject scored 1.5 SD below average on at least one memory testAge
Educational level
Baseline cognitive status
66 subjects (8.8%) had converted to MCI. The global incidence rate of MCI was 25.94/1,000 person-years. Persons with higher age (OR 1.08, 95% CI 1.01 to 1.16), APOE e4 allele carriers (OR 2.04, 95% CI 1.15 to 3.64) and persons with medicated hypertension (OR 1.86, 95% CI 1.05 to 3.29) were more likely to convert to MCI than those individuals of lower age and without an APOE e4 allele or medicated hypertension.
Staehelin et al., 1999369Community cohort (332)2 yearsAPOE genotypeComputerized test for free recall and information processing speed
Reaction time
WAIS-R vocabulary subtest – define 32 words
Educational level
At baseline:
Adjusting for age and education:
e4/4 and e3/4 performed lowest in free recall, reaction time, and WAIS-R vocabulary subtest compared to e3/3 or carriers of one or two e2 alleles (free recall P = 0.05; reaction time P = 0.009; WAIS-R vocabulary subtest P < 0.05)
No significant changes in any outcome measure (free recall, reaction time, or WAIS-R vocabulary subtest) after 2 years in any APOE genotype
Shadlen et al., 2005330Community cohort (HMO members) (2140)3.29 yearsAPOE genotypeChange in CASI scoreAge
Years of followup
Cerebrovascular disease
GEE analysis:
Risk factors associated with change in global cognitive performance
No e4 – reference
One e4 allele: coefficient = −0.23 (95% CI −2.5 to 2.05; P = 0.846)
Two e4 alleles: coefficient = −10.08 (95% CI−16.24 to −3.92; P = 0.001)
Yaffe et al., 1997370Clinical cohort - subjects in the multi- center Study of Osteoporotic Fractures (1248)6 yearsAPOE genotypeModified MMSE (max score 26)
Trails B
Cognitive decline was defined on each or any test if a woman had the largest 10th percentile reduction in performance from initial score to repeat testing
Educational level
Baseline cognitive status
Presence of severe tremor
Presence of an APOE e4 was significantly associated with worsening on all cognitive tests at followup compared to no e4 group (modified MMSE P = 0.01; DSST P = 0.05; Trails B P = 0.003)

Incidence of cognitive decline was 1.6 times higher in the e4 group (P < 0.03) and ranged from 1.2 times higher for Trails B to 2.4 times higher for modified MMSE. Homozygotes declined almost twice as fast as heterozygotes on all tests except Trails B.
Reduction on the modified MMSE was 0% for no e4; 1.9% for 1 e4; and 3.7% for 2 e4s (P < 0.001)
Reduction on DSST was 6.2% for no e4; 9% for 1 e4 and 17.5% for 2 e4s (P = 0.04)
Reduction on Trails B was 5.9% for no e4; 25% for 1 e4 and 10.9% on 2 e4s (P = 0.002)
Yaffe et al., 2009258Community cohort (2509)8 yearsAPOE genotypeSlopes of 3MS scores were estimated by best linear unbiased predictions using a linear mixed model with random intercepts and slopes. Slopes of 0 or greater were classified as maintainers. Those with predicted slopes less than 0, but not more than one SD below the mean of the slopes were classified as minor decliners. Those with predicted slopes more than 1 SD below the mean were classified as major decliners.Age
Educational level
APOE genotype
Minor vs. major decliners:
APOE e4: OR 2.31 (95% CI 1.75 to3.05)

APOE e4 was not associated with being a maintainer vs. a minor decliner: OR 0.8 (95% CI 0.62 to 1.02)
Carmelli et al., 1998262Community cohort (NHLBI WWII twin substudy) (410)10 to 25 yearsMid-life hyperglycemia (1- hour postprandial glucose > 200 or use of hypoglycemic agent or insulin)

APOE genotype
Change in test scores: MMSE, DSST, BVRTAge
Baseline scores
Incident cardiovascular disease
Mean change (SD)
APOEe4+ and hyperglycemia+:
MMSE: 1.66 (0.39)
DSST: 7.84 (1.08)
BVRT: 1.05 (0.26)

APOEe4+ and hyperglycemia−:
MMSE: 0.73 (0.28)
DSST: 4.47 (0.76)
BVRT: 0.53 (0.19)

APOEe4− and hyperglycemia+:
MMSE: 0.47 (0.2)
DSST: 4.14 (0.56)
BVRT: 0.84 (0.14)

APOEe4− and hyperglycemia−:
MMSE: 0.47 (0.16)
DSST: 3.34 (0.45)
BVRT: 0.37 (0.11)

All scores are significantly different from 0 and statistically significant at p < 0.05
Dik et al., 2000371Community cohort (1243)3.1 yearsAPOE genotypeMMSE; AVLT (3 trials); memory decline was defined as ≥1 SD mean change score on immediate recall, delayed recall, and retention based on AVLTAge
Educational level
APOE e4 carriers
APOE e4 non-carriers
MMSE 27–30 (normal cognition)
MMSE 21–26 (impaired cognition)
In subjects with MMSE 21–26 and APOE e4 (adjusted for age, sex, education and baseline recall scores):
Decline on immediate recall: OR 3.8 (95% CI 1.4 to 10)
Decline on delayed recall: OR 2.9 (1.2 to 7.0)
Decline on retention: OR 3.3 (1.1 to 10.1)

No association of decline in cognitively normal subjects with APOE e4
Packard et al., 2007284Clinical cohort (PROSPER trial) (5804)3.2 yearsAPOE genotypeMMSE, picture-word learning test, Stroop color word test, letter digit coding testAge
History of vascular disease
Antihypertensive medication
Treatment allocation
Baseline cognitive test scores
At baseline, subjects with APOE e4versus those without e4 had poorer memory performance (mean score difference −0.20 [95% CI −0.31 to −0.09] for immediate recall and −0.32 [−0.48 to − 0.16] for delayed recall) and slower information processing (difference in Stroop, 2.79 seconds [95% CI 1.20 to 4.28]; Letter-Digit score, −0.36 [−0.77 to 0.05]). Subjects with APOE e4 showed a greater decline in immediate (−0.22, 95% CI −0.33 to −0.11) and delayed (−0.30, −0.46 to −0.15) memory scores but no significant change in speed of information processing (Stroop P = 0.17; Letter-Digit P = 0.06).
Memory scores decreased 2.5% from baseline in those without e4, 4.3% in e4 heterozygotes (P = 0.01 for immediate and P = 0.03 for delayed, vs. no e4), and 8.9% to 13.8% in e4 homozygotes (P = 0.04 for immediate and P= 0.004 for delayed, vs. heterozygotes). APOE e4 was associated with greater decline in instrumental activities of daily living (P < 0.001).
Tyas et al., 2007183Community cohort (470)

Religious Orders Study
1–11 yearsAPOE genotypeSubjects performed four CERAD tests, MMSE and an ADL screen. Subjects with mild cognitive impairments had at least one specific area of impaired cognitive function, such as memory or naming, but had intact global cognitive ability and ADL.Age
Prior cognitive state
Transition from intact to MCI – APOEe4 present: OR 1.87 (95% CI 1.27 to 2.73)

Transition from intact to global impairment – APOEe4 present: OR 3.02 (1.87 to 4.89)

Abbreviations: 3MS = Modified Mini-Mental State Examination; ADL = activities of daily living; APOE = apolipoprotein E gene; APOE e2/e3/e4 = epsilon 2/3/4 allele of the apolipoprotein E gene; AVLT = Auditory Verbal Learning Test; BVRT = Benton Visual Retention Test; CASI = Cognitive Abilities Screening Instrument; CDR = Clinical Dementia Rating; CERAD = Consortium to Establish a Registry for Alzheimer’s Disease; CI = confidence interval; COWA = Controlled Oral Word Association test; CVLT = California Verbal Learning Test; DM = diabetes mellitus; DSST = Digit Symbol Substitution Test; DWR = Delayed Word Recall; GEE = Generalized estimated equations; HTN = hypertension; MCI = mild cognitive impairment; MI = myocardial infarction; MMSE = Mini-Mental State Examination; NS = not statistically significant; NSAIDs = non-steroidal anti-inflammatory drugs; OR = odds ratio; SD = standard deviation; SDMT = Symbol Digit Modalities Test; TIA = transient ischemic attack; Trails B = Trail Making Test Part B; WAIS-R = Wechsler Adult Intelligence Scale-Revised; WF = Word Fluency Test

From: 3, Results

Cover of Preventing Alzheimer's Disease and Cognitive Decline
Preventing Alzheimer's Disease and Cognitive Decline.
Evidence Reports/Technology Assessments, No. 193.
Williams JW, Plassman BL, Burke J, et al.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.