TABLE 1.

Summary of Studies Relating APOE Genotype with LOAD Endophenotypes

Author	Subjects	Age in years, mean (range)	Endophenotype	Finding
AGE AT ONSET
Lehtovirta et al.,¹¹⁷ 1995	202 Finnish LOAD patients and 55 age- and sex-matched controls	Disease onset: ε4: −/− 76 ± 10, −/+: 77 ± 8, +/+: 71 ± 7	Age at onset	Age at onset decreased from 76 to 69 as the number of ε4 alleles increased from 0 to 2
Gomez-Isla et al.,¹⁶ 1996	359 patients LOAD, age- and sex-matched 129 controls	LOAD group: mean age of 77.8 years; control group: mean age of 77.8 years	Age at onset	Age of onset declined significantly as number of ε4 alleles increased (P < 0.0001 for linear contrast ε3/ε3 to ε3ε4 to ε4/ε4
Holmes et al.,¹⁷ 1996	164 patients	60 years and older	Age at onset	Trend for decreasing age at onset of 3–4 years in carriers of the APOEε4 –allele (mean age [SD]: no ε4− versus ε4: 78.7 [7.9] versus 75.5 [5.9], P = 0.004)
Murman et al.,²⁰ 1996	107 normal, elderly control subjects and 123 LOAD patients	45 years and older	Age at onset	Increased APOEε4 frequencies associated with onset ages of 55 and 75 years, but not at the extremes of onset ages (i.e., onset between 45 and 54 years of age and after age 75)
Breitner et al.,¹⁴ 1999	5677 elderly residents of Cache County, Utah	65 years and older	Prevalence and Age at onset	Age-specific prevalence of LOAD reached in APOEε4 heterozygotes the maximum at age 87, in homozygotes at age 73 and in noncarriers at age 95
Tang et al.,²³ 1996	305 LOAD patients, 485 nondemented controls	LOAD cases: 76.4 ± 9.1 years, controls: 72.9 ± 6.7 years	Relative risk of LOAD, Age at onset	Relative risk (RR) for LOAD associated with APOEε4 homozygosity increased in all ethnic groups (African-American RR = 3.0; 95% confidence interval [CI] = 1.5–5.9; Caucasian RR = 7.3, 95% CI = 2.5–21.6; and Hispanic RR = 2.5, 95% CI = 1.1–5.7), compared with those with APOE-ε3/ε3 genotypes. The risk was also increased for APOE-ε4 heterozygous Caucasians (RR = 2.9, 95% CI = 1.7–5.1) and Hispanics (RR = 1.6, 95% CI = 1.1–2.3), but not for African-Americans (RR = 0.6, 95% CI = 0.4–0.9). The age distribution of the proportion of Caucasians and Hispanics without LOAD was consistently lower for ε4 homozygous and heterozygous individuals than for those with other APOE genotypes
Kurz et al.,¹⁹ 1996	91 patients, 69 healthy age-matched controls	44–95 years	Age at onset	Inheritance of at least one ε4 allele associated with significant reduction of age at onset by 7.7 years among patients 83 years or older, and a weaker relationship among patients aged 44–63 years
Poirier et al.,²¹ 1993	91 patients with LOAD and 74 controls	Mean age (SD): 75.1 (10.3)	Prevalence of LOAD, Age at onset	Significant association between ε4 and sporadic LOAD (ε4 frequency 0.380 in LOAD and 0.122 in controls, P < 0.01). Age at onset in ε4 carriers earlier than in ε2 or ε4 carriers
Mak et al.,⁴⁷ 1996	65 LOAD patients and 82 controls	Mean age of 76.5 years	Age at onset	Tendency toward lower age at onset in subjects with 1 or 2 copies of ε4 (mean age of onset [SD] −/− versus 4/− versus 4/4: 73.3 [8.5] versus 72.0 [6.4] versus 71.2 [5.0]), and higher in subjects with ε2/ε2 or ε2/ε3 than in subjects with ε3/ε3 but differences not statistically significant (P = 0.078, Z = 1.419)
do Couto et al.,⁴⁹ 1998	68 patients with LOAD	Mean age (SD): 68.8 (7.9)	Age at onset	Age at onset significantly higher in patients bearing the APOEε4 allele (ε3/ε4 and ε4/ε4, 65.7 [7.1], n = 40) compared with patients without ε4 allele (ε3/ε3, 61.6 [7.6], n = 28, P < 0.05)
Dal Forno et al.,⁵⁰1996	101 LOAD subjects	Mean age: 69.6 years	Age at onset	Age at onset highest for ε4 heterozygous subjects and least for ε4 negative subjects. Heterozygous subjects declined more rapidly on MMSE and the Category Fluency Test than subjects without ε4 or ε4 homozygosity
COGNITIVE PERFORMANCE
Welsh-Bohmer et al.,⁵¹ 2008	507 participants of the Cache County Study of Memory in Aging (CCMS)	70–110 years	Cognitive performance	No association
Salo et al.,⁵² 2001	46 nondemented persons	>85 years	Memory performance	No association
Murphy et al.,⁵³ 1997	86 subjects with LOAD	Mean age of onset (SD): based on caregiver report: 65.3 (7.4); based on age when MMSE < 23: 68.8 (7.0)	Rate of decline on MMSE	No association
Cosentino et al.,⁵⁴ 2008	One incident (n = 199) and 2 prevalent samples (n = 215, n = 156) of LOAD patients	Age 65 years and older	Memory performance	Presence of an APOE ε4 allele associated with a more rapid decline in memory perfomance over a 7-year follow-up period
Wehling et al.,⁴⁶ 2007	70 LOAD patients	50–75 years	Cognitive performance	APOEε4 carriers had slightly poorer performance than noncarriers on the MMSE (27.5 versus 28.4, P = 0.03) and learning trials of the California Verbal Learning Test (CVLT) (F [1,68] = 5.46, P = 0.022)
Hirono et al.,⁵⁵ 2003	64 LOAD patients	60 years or older	Memory performance	Presence of the APOEε4 allele in dose–response fashion associated with accelerated memory decline on Word Recall subtest of ADAS-Cog (mean score −/− versus 4/− versus 4/4: −0.2 versus 0.4 versus 1.0, P = 0.008)
Mayeux et al.,⁵⁶ 2001	563 healthy elderly without LOAD or questionable dementia	65 years and older	Memory performance over 7-year follow-up	APOEε4 allele associated with a more rapid decline in memory performance
Wilson et al.,⁵⁷ 2002	669 participants from the Religious Order Study	65 years and older	Summary measures of episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability	Average annual increase of 0.016 units in the ε2 subgroup and annual decreases of 0.022 units in those with ε3/3 and of 0.073 units in the ε4 subgroup
Lehmann et al.,⁵⁸ 2006	2181 elderly of the Hordaland Health Study	70–74 years	Episodic memory	APOEε4 effect on episodic memory: OR of cognitive impairment in women 1.8 (95% CI: 1.1–2.8) for heterozygotes and 1.1 (0.3–3.7) for homozygotes; OR in men 1.1 (95% CI 0.6–2.1) for heterozygotes and 10.7 (95% CI 4.7–24) for homozygotes
Liu et al.,⁴⁴ 2008	2208 related individuals	50 years and older	Cognitive performance	APOEε4 significantly associated with reduced test scores for Adult Verbal Learning Test, particularly on the memory and learning subdomains
Bondi et al.,⁵⁹ 1995	52 elderly nondemented	59–83 years	Performance on California Verbal Learning Test (CVLT)	APOEε4 associated with poorer performance on CVLT. Six of the 14 APOEε4 subjects developed either LOAD or questionable LOAD, whereas none of the 26 non-APOEε4 subjects demonstrated any cognitive decline
Dik et al.,⁶⁰ 2001	1168 subjects from the population-based Longitudinal Aging Study Amsterdam	62–85 years	Performance on MMSE, immediate recall and delayed recall, and the Alphabet Coding Task-15	APOEε4 carriers had a greater rate of cognitive decline shown by MMSE scores and slower information processing speeds after 6 years. The effects of both memory complaints and APOEε4 allele carriage were additive: subjects with both factors had a two times higher cognitive decline than did subjects without both factors
Hsiung et al.,⁶¹ 2004	1469 cases with cognitive impairment, 582 controls	Control group: mean age 75.6, group with CIND: mean age 77.8, group with AD: mean age 82.7	Progression from normal cognition to CIND and from CIND to AD or vascular dementia, age at onset of LOAD	Possession of an APOEε4 allele associated with increased risk of LOAD developing from CIND (OR 2.6, 95% CI 1.48–4.92), and associated with decrease in the age at onset of LOAD
Petersen et al.,⁶² 1995	66 patients with MCI from Mayo Clinic	Mean age: 79.8 years	Conversion from MCI to dementia	APOEε4 strong predictor for conversion to dementia
Caselli et al.,⁴² 1999	100 nondemented individuals	Mean age 56 years	Immediate and delayed recall	Tests sensitive to immediate and delayed recall showed significant negative correlation with age in the APOEε4 homozygote group relative to the noncarrier group
Flory et al.,⁴³ 2000	220 nondemented non-Hispanic Caucasian men and women	Aged 24–60 (average age = 46)	Verbal learning and memory (e.g., learning a list of words and recalling them 30 min later), visual memory (e.g., reproducing a previously copied figure from memory), and attention span memory	Performance on learning and memory tasks was significantly poorer in adults having any APOEε4 allele, relative to adults with APOEε2 or APOEε3 genotypes (P < 0.01)
Reynolds et al.,⁶³ 2006	478 nondemented twins from the Swedish Adoption/Twin Study of Aging (SATSA)	50 years and older	Memory performance over 13 years	APOEε4 associated with working and recall memory ability levels and working memory rate of change, with ε4 homozygotes exhibiting the worst performance at all ages over 13-year follow-up
Schultz et al.,⁴⁵ 2008	626 male twins randomly drawn from the Vietnam Era Twin (VET) Registry	In their 50s	Memory performance	ε4-carriers: lower performance on immediate and delayed recall than noncarriers (mean [SD] comparing ε4+ versus ε4−: immediate recall 22.19 [5.37] versus 23.8 [6.2]; delayed recall: 19.5 [5.9] versus 20.12 [6.6])