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. Author manuscript; available in PMC: 2010 Jan 28.
Published in final edited form as: Neuroscience. 2009 Apr 9;164(1):174–190. doi: 10.1016/j.neuroscience.2009.04.006

Table 2.

Relation between APOE genotype and LOAD endophenotypes

Author Subjects Age in y, mean (range) Endophenotype Finding
Age-at-onset
  Lehtovirta et al., 1995 202 Finnish LOAD
  patients and 55 age-
  and sex-matched
  controls		 Disease onset: ε4: −/−
  76±10, −/+: 77α8,
  2,+/+ 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., 1996 359 Patients LOAD, age
  and sex matched 129
  controls		 LOAD group: mean age
  of 77.8 y; control
  group: mean age of
  77.8 y		 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., 1996 164 Patients 60 y And older Age-at-onset Trend for decreasing age-at-onset of 3–4 y
  in carriers of the APOEε4 allele (mean
  age (SD): no ε4-vs ε4: 78.7 (7.9) vs. 75.5
  (5.9), P=0.004))
  Murman et al., 1996 107 Normal, elderly
  control subjects and
  123 LOAD patients		 45 y And older Age-at-onset Increased APOEε4 frequencies associated
  with onset ages of 55 and 75 y, but not at
  the extremes of onset ages (i.e. onset
  between 45 and 54 y of age and after age
  75)
  Breitner et al., 1999 5677 Elderly residents of
  Cache County, Utah		 65 y 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
  non-carriers at age 95
  Tang et al., 1996 305 LOAD patients, 485
  nondemented controls		 LOAD cases: 76.4±9.1
  y, controls: 72.9±6.7
  y		 Relative risk of LOAD,
  age-at-onset		 RR for LOAD associated with APOEε4
  homozygosity increased in all ethnic
  groups (African American relative risk
  [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-epsilon 3/epsilon 3 genotypes. The
  risk was also increased for APOE-epsilon
  4 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., 1996 91 Patients, 69 healthy
  age-matched controls		 44–95 y Age-at-onset Inheritance of at least one ε4 allele
  associated with significant reduction of
  age-at-onset by 7.7 y among patients 83 y
  or older, and a weaker relationship among
  patients aged 44–63 y
  Poirier et al., 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., 1996 65 LOAD patients and
  82 controls		 Mean age of 76.5 y Age-at-onset Tendency towards lower age-at-onset in
  subjects with one or two copies of ε4
  (mean age-of-onset (SD) −/− vs. 4/− vs.
  4/4: 73.3 (8.5) vs. 72.0 (6.4) vs. 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., 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.,1996 101 LOAD subjects Mean age: 69.6 y 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-Bomer et (l), 2008 507 Participants of the
  CCMS		 70–110 y Cognitive performance No association
  Salo et al., 2001 46 Nondemented
  persons		 >85 y Memory performance No association
  Murphy et al., 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., 2008 One incident (n=199)
  and two prevalent
  samples (n=215,
   n=156) of LOAD
  patients		 Age 65 y and older Memory performance Presence of an APOE ε4 allele associated
  with a more rapid decline in memory
  performance over a 7-year follow-up
  period
  Wehling et al., 2007 70 LOAD patients 50–75 y Cognitive performance APOEε4 carriers had slightly poorer
  performance than non-carriers on the MMSE
  (27.5 vs. 28.4, P=0.03) and learning trials of
  the CVLT (F(1,68)=5.46, P=0.022)
  Hirono et al., 2003 64 LOAD patients 60 y 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
  −/− vs. 4/− vs. 4/4: −0.2 vs. 0.4 vs. 1.0,
  P=0.008)
  Mayeux et al., 2001 563 Healthy elderly
  without LOAD or
  questionable dementia		 65 y And older Memory performance
  over 7-year follow-up		 APOEε4 allele associated with a more rapid
  decline in memory performance
  Wilson et al., 2002 669 Participants from
  Religious Order Study		 65 y 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
  Lehman et al., 2006 2181 Elderly of the
  Hordaland Health
  Study		 70–74 y 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., 2008 2208 Related individuals 50 y 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., 1995 52 Elderly non-demented 59–83 y Performance on 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., 2001 1168 Subjects from the
  population-based
  Longitudinal Aging
  Study Amsterdam		 62–85 y 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 y. 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., 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
  VaD, 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., 1995 66 Patients with MCI
  from Mayo Clinic		 Mean age: 79.8 y Conversion from MCI
  to dementia		 APOEε4 strong predictor for conversion to
  dementia
  Caselli et al., 1999 100 Nondemented
  individuals		 Mean age 56 y 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., 2000 220 Non-demented 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., 2006 478 Non-demented twins
  from the SATSA		 50 y And older Memory performance
  over 13 y		 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., 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 non-carriers (mean
  (SD) comparing ε4+ vs. ε4−: immediate
  recall 22.19 (5.37) vs. 23.8 (6.2); delayed
  recall: 19.5 (5.9) vs. 20.12 (6.6))