8.1. APOE-Related Therapeutic Response to a Multifactorial Therapy in Alzheimer’s Disease
Patients with dementia (N=765, age: 69.44 ± 9.15 years, range: 50-96 years; 466 females, age: 69.18 ± 9.19 years, range: 50-96 years; and 299 males, age: 69.85 ± 9.09 years, range: 50-91 years; p < 0.01) received for three months a multifactorial therapy integrated by CDP-choline (500 mg/day, p.o.), Nicergoline (5 mg/day, p.o.), Sardilipin (E-SAR-94010)(LipoEsar®)(250 mg, t.i.d.), and Animon Complex® (2 capsules/day), a nutraceutical compound integrated by a purified extract of Chenopodium quinoa (250 mg), ferrous sulphate (38.1 mg equivalent to 14 mg of iron), folic acid (200 µg), and vitamin B12 (1 µg) per capsule (RGS: 26.06671/C). Patients with chronic deficiency of iron (<35 µg/mL), folic acid (<2.5 ng/mL) or vitamin B12 (<150 pg/mL) received an additional supplementation of iron (80 mg/day), folic acid (5 mg/day) and B complex vitamins (B1, 15 mg/day; B2, 15 mg/day; B6, 10 mg/day; B12, 10 µg/day; nicotinamide, 50 mg/day), respectively, to maintain stable levels of serum iron (50–150 µg/mL), folic acid (5–20 ng/mL) and vitamin B12 levels (500–1000 pg/mL) in order to avoid the negative influence of all these metabolic factors on cognition [102,103]. Patients with hypertension (>150/85 mmHg) received Enalapril (20 mg/day). The frequency of APOE genotypes was: APOE-2/3, 7.97%; APOE-2/4, 1.18%; APOE-3/3, 58.95%; APOE-3/4, 27.32%; and APOE-4/4, 4.58% (Figure 1). Blood pressure, psychometric assessment (Mini-Mental State Examination, MMSE; ADAS; Hamilton Rating Scale-Depression, HAM-D; Hamilton Rating Scale-Anxiety, HAM-A), and blood parameters (glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglyceride, iron, folate, vitamin B12, TSH, T4) were evaluated at baseline and after 3 months of treatment.
Systolic (p < 0.0002) and diastolic blood pressure (p < 0.001), cognitive function (as assessed by MMSE, 20.51 ± 6.51 vs. 21.45 ± 6.95, p < 0.0000000001; ADAS-Cog, 22.94 ± 13.87 vs. 21.23 ± 12.84, p < 0.0001; ADAS-Non-Cog, 5.26 ± 4.18 vs. 4.15 ± 3.63, p < 0.0000000001; ADAS-Total, 27.12 ± 16.93 vs. 24.28 ± 15.06, p < 0.00009), and mood (HAM-A, 11.35 ± 5.44 vs. 9.79 ± 4.33, p < 0.0000000001; HAM-D, 10.14 ± 5.23 vs. 8.59 ± 4.30, p < 0.0000000001) improved after treatment. Glucose levels did not change. Total cholesterol levels (224.78 ± 45.53 vs. 203.64 ± 39.69 mg/dL, p < 0.0000000001), HDL-cholesterol levels (54.11 ± 14.54 vs. 52.54 ± 14.86 mg/dL, p < 0.0001), and LDL-cholesterol levels (148.15 ± 39.13 vs. 128.89 ± 34.83 mg/dL, p < 0.0000000001) were significantly reduced, whereas triglyceride levels increased (111.99 ± 67.14 vs. 120.69 ± 67.14 mg/dL, p < 0.0006) after 3 months of combined treatment. Folate (7.07 ± 3.61 vs. 18.14 ± 4.23 ng/mL, p < 0.000000001) and vitamin B12 levels (459.65 ± 205.80 vs. 689.78 ± 338.82 pg/mL, p < 0.000000001) also increased, and both TSH and T4 levels remained unchanged after treatment. The response rate in terms of cognitive improvement was as follows: 59.74% responders (RRs), 24.44% non-responders (NRs), and 15.82% stable responders (SRs)(no change in MMSE score after three months of treatment). The response rate in cholesterol levels was very similar: 57.78% RRs, 28.50% NRs, and 13.72% SRs. 
In this study, the basal MMSE score differed in APOE-2/3 carriers with respect to APOE-2/4 (p < 0.02), APOE-3/4 (p < 0.004), and APOE-4/4 carriers (p < 0.0009); in APOE-3/3 vs. APOE-3/4 (p < 0.0005), and APOE-3/3 vs. APOE-4/4 (p < 0.002). The best responders were APOE-3/3 (p < 0.0000000001) > APOE-3/4 (p < 0.00001) > APOE-4/4 carriers (p < 0.05). Patients harboring the APOE-2/3 and APOE-2/4 genotypes did not show any significant improvement. The response rate by genotype was the following: APOE-2/3: 44.26% RRs, 36.07% NRs, 19.67% SRs; APOE-2/4: 55.56% RRs, 44.44% NRs, 0.0% SRs; APOE-3/3: 63.42% RRs, 21.06% NRs, 15.52% SRs; APOE-3/4: 56.94% RRs, 27.75% NRs, 15.31% SRs; APOE-4/4: 51.43% RRs, 28.57% NRs, 20.00% SRs. 
Systolic blood pressure (SBP) was significantly reduced in patients with the APOE-3/3 (p < 0.00007) and APOE-3/4 genotypes (p < 0.01), and diastolic blood pressure exhibited a similar pattern (APOE-3/3, p < 0.005; APOE-3/4, p < 0.01), with no changes in either SBP or DBP in APOE-2/3, APOE-2/4 and APOE-4/4 carriers.
Figure 1  APOE-Related total cholesterol levels response to a multifactorial therapy in patients with dementia.    Glucose levels tended to decrease in APOE-4 allele carriers, but only patients with the APOE-3/4 genotype showed a significant reduction in glucose levels (p < 0.02). In contrast, APOE-2/3 carriers showed a tendency to increased glucose levels.