Table 1 Studies investigating the effects of APOE4 on the rate of cognitive decline in AD patients

Cosentino et al. [15]

570 AD patients (WHICAP and Predictors Study cohorts) were recruited and followed for an average of 4 years. Outcome variable was a composite cognitive z-score from five cognitive domains (memory, abstract reasoning, visuospatial, language, and executive speed).

Mean age for two population-based cohorts (WHICAP) and one clinic-based cohort (Predictors Study) participants was 81.97 (n = 199; 73% female, 61% Hispanic, 31% African American), 80.70 (n = 215; 76% female, 62% Hispanic, 28% African American), and 75.30 (n = 156; 58% female, 0% Hispanic, 5% African American) years of age, respectively.

The effect of APOE4 on rate of cognitive decline varied across samples. APOE4+ AD patients in the incident sample demonstrated an accelerated rate of cognitive decline compared to APOE4− AD patients. Caucasian participants were more likely to show an association between APOE4 status and rate of cognitive decline as compared to Hispanic and African American participants.

Martins et al. [16]

218 AD patients (OPTIMA cohort) were evaluated for cognitive ability using the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX) scale.

Mean age for APOE4/4 was 71.1 (n = 28, 55% female), APOE3/4 was 73 (n = 97; 54% female), APOE2/4 was 75.8 (n = 8; 75% female), APOE3/3 was 75.2 (n = 69; 55% female), APOE2/3 was 74.2 (n = 15; 53% female), and APOE2/2 was 79.5 (n = 1; 100% female). No ancestry information was provided.

APOE4+ AD patients demonstrated both an earlier and faster rate of cognitive decline compared to APOE4− AD patients. APOE4/4 patients progressed faster than APOE3/4 patients.

Craft et al. [17]

201 probable AD patients were evaluated using the Dementia Rating Scale (DRS) and followed for 1–6 years to measure the rate of cognitive decline.

Mean age for APOE4/4 was 74.0 (n = 30; 77% female), APOE3/4 was 78.6 (n = 82; 59% female), APOE3/3 was 79.8 (n = 75; 60% female), and APOE2/3 was 77.3 (n = 14; 36% female). No ancestry information was provided.

APOE4/4 AD patients demonstrated an accelerated rate of cognitive decline compared to APOE4− AD patients.

Hirono et al. [18]

64 AD patients were evaluated using the ADAS-Cog and followed for 1 year to measure the rate of cognitive decline.

Mean age for APOE4+ homozygotes was 70.8 (n = 8; 25% female), APOE4+ heterozygotes was 73.6 (n = 33; 83% female), and APOE4− was 76.3 (n = 23; 74% female). No ancestry information was provided.

APOE4+ AD patients demonstrated an accelerated rate of amnestic (assessed by word recall and recognition subtests) and overall cognitive decline, which was significantly correlated with the number of APOE4 alleles.

Kanai et al. [19]

33 AD patients were evaluated with the Mini-Mental State Examination (MMSE) and CSF biomarkers, and followed for up to 20 months to measure the rate of cognitive decline.

Mean age for both APOE4+ (n = 17; 59% female) and APOE4− (n = 16; 69% female) AD patients was 65. No ancestry information was provided.

APOE4+ AD patients demonstrated a more rapid decrease in MMSE score, as well as increased levels of CSF tau compared to APOE4− AD patients.

Chang et al. [20]

104 AD patients (ADNI cohort) and 123 controls were evaluated for neuropsychological and morphometric changes stratified by age (young-old vs. very-old) and APOE4 status.

Mean age of young-old APOE4+ AD patients was 70.84 (n = 49; 57% female), very-old APOE4+ AD patients was 83.70 (n = 20; 25% female), young-old APOE4− AD patients was 70.53 (n = 15; 53% female), and very-old APOE4− AD patients was 84.16 (n = 20; 60% female). No ancestry information was provided.

Young-old (≤ 75 years old) APOE4+ AD patients demonstrated greater cognitive decline in memory and language over a 1-year interval as compared to other groups, suggesting that the effect of APOE status on rate of decline is dependent upon age at onset of disease.

Kleiman et al. [21]

366 AD patients were evaluated with the MMSE, ADAS-Cog, and daily function scales (Instrumental Activities of Daily Living, IADL; Alzheimer’s Disease Cooperative Study-Activities of Daily Living, ADCS-ADL), and followed for up to 1.8 years to measure the rate of cognitive decline.

Mean age for APOE4+ homozygotes was 71.6 (n = 51; 70.6% female), APOE4+ heterozygotes was 74.4 (n = 159; 59.1% female), and APOE4− was 73.4 (n = 156; 59.6% female). No ancestry information was provided.

APOE4 status did not influence the rate of disease progression in either cognitive or functional domains of assessment, regardless of allele dose.

Growdon et al. [22]

66 probable AD patients were evaluated using nine cognitive tests assessing explicit memory, attention, language, visuospatial function, frontal-lobe function, and logical reasoning abilities for up to 5.5 years to measure the rate of cognitive decline.

56% of study participants were female. Mean age for APOE4+ homozygotes was 68.6 (n = 16), APOE4+ heterozygotes was 70.3 (n = 34), and APOE4− was 65.5 (n = 16). No ancestry information was provided.

APOE4 status did not influence the rate of cognitive decline across APOE genotypes.

Holmes et al. [23]

164 late-onset AD patients were evaluated for cognitive and non-cognitive abilities to measure the rate of cognitive decline.

Mean age for APOE4+ AD patients was 75.5 (n = 92) and APOE4− AD patients was 78.7 (n = 72). No ancestry information was provided.

APOE4 status was found to be associated with an earlier age of onset, but was not found to influence the cognitive progression of the disease.

Kurz et al. [24]

64 AD patients were evaluated using the Cambridge Cognitive Examination (CAMCOG), the MMSE, and the Dementia Scale (DS) included in the CAMDEX, and followed for over 3 years to measure the rate of cognitive decline.

The study included 14 males and 50 females, with an average age of 73. No ancestry information was provided.

APOE4 status was found to have no significant impact on the rate of deterioration in everyday performance, the rate of cognitive decline, or on baseline function and progression of the disease.

Basun et al. [25]

60 late-onset AD patients were evaluated using the MMSE over 3 years to measure the rate of cognitive decline.

Mean age for APOE4+ AD patients was 81.6 (n = 27; 85% female) and APOE4− AD patients was 85.8 (n = 33; 82% female). No ancestry information was provided.

APOE4+ AD patients demonstrated a significantly lower age at disease onset and longer duration, but no significant differences were found in the MMSE test scores over time between carriers and non-carriers.

Murphy et al. [31]

86 probable AD patients were evaluated using the Mini-Mental State Examination (MMSE) over an average of 3.6 years to measure the rate of cognitive decline.

Participant details not available.

No association between APOE4 allele dosage and rate of cognitive decline was found.

Farlow et al. [26]

959 AD patients were treated with either metrifonate or placebo for a period of up to 26 weeks to measure the effects of treatment and APOE4 status on cognitive decline using the ADAS-Cog and Clinician’s Interview-Based Impression of Change with Caregiver Input (CIBIC-Plus).

Mean age (placebo) for APOE4+ homozygotes was 70.5 (n = 59; 62.7% female, 69.5% Caucasian), APOE4+ heterozygotes was 74.1 (n = 183; 67.2% female, 72.1% Caucasian), and APOE4− was 73.2 (n = 132; 57.6% female, 73.5% Caucasian). Mean age (metrifonate) for APOE4+ homozygotes was 72.1 (n = 68; 57.4% female, 77.9% Caucasian), APOE4+ heterozygotes was 74.4 (n = 281; 67.3% female, 80.4% Caucasian), and APOE4− was 73.5 (n = 236; 61.4% female, 78.8% Caucasian).

APOE4 genotype in conjunction with metrifonate treatment had no significant effect on global function and cognitive performance in AD patients. APOE4 genotype was not found to influence the rate of disease progression in placebo-treated AD patients.

Aerssens et al. [27]

1528 probable AD patients were treated with either galantamine or sabeluzole or placebo for a period of up to 1 year to measure the effects of treatment and APOE4 status on cognitive decline using the MMSE and ADAS-cog, along with the Disability Assessment for Dementia (DAD).

Mean age was 74.2 (59% female). No ancestry information was provided.

APOE4/4 AD patients demonstrated a lower age of disease onset, but allele status did not influence the rate of cognitive decline (including in placebo-treated group), or the effectiveness of galantamine treatment.

Stern et al. [28]

99 probable AD patients (WHICAP cohort) were evaluated using a modified MMSE, as well as other cognitive and motor measures, and were followed biannually for up to 6 years to measure the rate of cognitive decline.

Mean age for APOE4+ homozygotes was 69.7 (n = 15; 66.7% female, 80% Caucasian, 20% African American), APOE4+ heterozygotes was 71.8 (n = 41; 43.9% female, 82.9% Caucasian, 4.9% African American, and 12.2% Hispanic), and APOE4− was 71.3 (n = 43; 44.2% female, 100% Caucasian).

APOE4+ AD patients demonstrated a lower rate of mortality, slower rate of decline in MMSE scores, less brain atrophy, and a delayed development of myoclonus than APOE4− AD patients. The presence of APOE4 allele was associated with an earlier age of onset of AD.

Frisoni et al. [29]

62 sporadic late-onset (≥ 70 years of age) AD patients were evaluated using the MMSE and Clinical Dementia Rating (CDR) to measure the relationship between disease progression and APOE4 status.

Mean age of APOE4+ homozygotes was 78.6 (n = 19; 74% female), APOE4+ heterozygotes was 79.8 (n = 16; 81% female), and APOE4− was 80.7 (n = 27; 93% female). No ancestry information was provided.

APOE4+ AD patients demonstrated a longer disease duration compared to APOE4− AD patients.

Hoyt et al. [30]

189 probable AD patients were evaluated using individual growth curve analyses for up to 2 years to measure the rate of cognitive decline using various neuropsychological tests.

Mean age for APOE4+ homozygotes was 69.2 (n = 22; 91% female), APOE4+ heterozygotes was 72.7 (n = 82; 79% female) and APOE4− was 73.2 (n = 47; 68% female). No ancestry information was provided.

APOE4/4 AD patients demonstrated a slower rate of decline on global cognitive functioning, but not for measures of specific cognitive functions.