Precision Medicine Treatment of Alzheimer’s Disease: Successful Randomized Controlled Trial

Introduction

Methods

Participants

Of 139 patients screened for trial participation eligibility, 66 (47%) failed the screening, over half of which was due to clinical and/or cognitive scores outside of the criteria presented below (see Figure 1 for flowchart summarizing patient selection and Supplemental Table S1 for detailed screening failure reasons). Seventy-three patients with MCI or early dementia, ages 45-76, were recruited to six clinical sites: Walnut Creek, California; San Rafael, California; Folsom, California; Hollywood, Florida; Rocky River, Ohio; and Nashville, Tennessee. Patients were recruited to the nine-month trial, and randomized to either the PM approach or SOC treatment arm. The random codes as well as the replacement random codes for this study were generated from Proc Plan based on the 2:1 randomization (PM:SOC) with specific seed numbers using SAS version 9.4 software. This resulted in treatment arm n’s of PM=50 and SOC=23.

Seven patients from the PM treatment arm prematurely dropped out of the study (three of which were due to issues or concerns with compliance with the intervention, two related to study partner health issues, and two related to participant voluntary decision to discontinue). Demographics and primary cognitive endpoints at baseline were comparable between precision medicine patients who dropped out and completed the study (Supplemental Table S2). Six participants were homozygous for ApoE4, 26 were heterozygous for ApoE4, 30 were homozygous for ApoE3, and 4 were heterozygous for ApoE2 and ApoE3. Demographics are listed in Table 1.

Inclusion criteria. Age 45-76 years; cognitive impairment, as demonstrated by complaints of cognitive decline plus a combination of Alzheimer’s Questionnaire (AQ-21) >4 and either Montreal Cognitive Assessment (MoCA) of 18-26 or two or more scores on CNS Vital Signs <50th percentile (neurocognitive index, executive function, verbal memory, visual memory, or composite memory). Thus, all patients had symptomatic cognitive decline as well as multiple areas of impairment, as judged by their significant others or study partners, as well as cognitive testing indicative of MCI or early-stage dementia.

Exclusion criteria. MoCA score <18 at baseline; uncontrolled major medical illness such as seizures, cardiovascular disease, cancer diagnosis within the past five years (excluding non-melanoma skin cancers), or any history of breast cancer (excluding ductal carcinoma in situ) or prostate cancer; a positive blood test for human immunodeficiency virus, hepatitis C, or syphilis; a major psychiatric diagnosis that affected activities of daily living; ongoing use of psychoactive medications known to impact cognition; ongoing anticoagulant therapy or history of deep vein thrombosis; MRI findings of hydrocephalus, cerebral infarct, extensive white matter disease consistent with multiple sclerosis, or intracranial neoplasm; symptomatic traumatic brain injury; lack of study partner (family member or care partner); inability to exercise; lack of computer access; pregnancy; diagnosis of a neurodegenerative disease other than Alzheimer’s (e.g., frontotemporal dementia); previous or ongoing treatment for MCI or dementia with the PM approach used here or a very similar approach; menopausal and perimenopausal women who were unwilling or unable to use bioidentical hormone replacement therapy, or men who were unwilling or unable to use testosterone replacement therapy; any contraindication to enclosed MRI; off-label use of donepezil; unwillingness to remediate or move away from identified sources of environmental toxicity (e.g., mycotoxins); or unwillingness to forgo alcohol (other than up to two small servings weekly of dry red wine).

Results

Metabolic Effects

Table 2 lists metabolic parameters prior to, and at the conclusion of, the 9 months of treatment. Relative to the SOC group, the PM group evidenced a statistically superior reduction in glycation (as a reduction in hemoglobin A1c) and insulin resistance (as HOMA-IR, homeostasis model assessment-estimated insulin resistance). Significant incremental improvements in lipid profile (as reduction in triglyceride-to-high-density-lipoprotein ratio), body mass index (BMI), systolic blood pressure, and methylation (as reduction in homocysteine) were also observed. Lastly, a significant increase in serum vitamin D was observed (as serum 25-hydroxycholecalciferol) in the precision medicine group. Whereas the PM group evidenced significant positive change from baseline in most biochemical markers, the only change observed for the SOC group was an increase in BMI over the study period.

^‡p≤.001, ^†p<.05, ^‖p≤.10 *BMI significantly increased for the standard of care group (p=.002). ^aCohen’s d and p-values estimated from Wilcoxon signed-rank tests to compare medians (month 9 vs. month 0) within each group. BP, blood pressure. ^bd and p-values estimated from Mann-Whitney U tests comparing median change (i.e., from month 0 to month 9) between groups. Month 0 values were subtracted from month 9 to compute delta scores, where positive values indicate increase and negative indicate decrease in lab value. Statistically significant effect sizes (d) appear bold. HbA1c: hemoglobin A1c; HOMA-IR: homeostasis model assessment-estimated insulin resistance, calculated based on fasting insulin and fasting glucose (fasting insulin in mIU/L times fasting glucose in mg/dL, divided by 405.45); HsCRP, high-sensitivity C-reactive protein. IQR: interquartile range; TG:HDL ratio: serum triglyceride-to-HDL (high-density lipoprotein) ratio. Vitamin D was measured as 25-hydroxycholecalciferol. Post-treatment tests were taken at the conclusion of the 9-month protocol for each patient, as described in the text.

Cognitive Function and Clinical Symptom Outcomes

Table 3 presents descriptive statistical information for cognitive and clinical outcomes over the study period (months 0 [baseline], 3, 6, and 9), as well as GLM findings. Table 4 provides detailed statistics for within-group change from baseline and between-group comparison of such. The AQ-C is a subjective change scale that is derived from the AQ-21. In the PM group, the AQ-C improved by 8.74 ± 10.35 points, whereas in the SOC group, the AQ-C declined by 2.36 ± 4.41 points, indicating that the partners of the PM group noted improvement, whereas those of the SOC group noted decline. The AQ-C GLM model interaction term was statistically significant and yielded a practically meaningful large effect (p<0.001, ${\eta }_p^2$=.211). AQ-C results are graphed in Figure 2. Similarly, the CST change differed between the two groups, reflecting improvement in the PM group but only minimal improvement in the SOC group, with a p-value<0.001 and an incremental effect size of d=0.231 (Figure 3 and Table 4). The GLM model interaction was statistically significant and yielded a clinically meaningful large effect (p<0.001, ${\eta }_p^2$=.231). PROMIS-10-Physical Health (Figure 4) and PROMIS-10-Mental Health (Figure 5) also showed significant improvements, with significant and large magnitude GLM model interaction effects p=0.002 (${\eta }_p^2$=.193) and p<0.001 (${\eta }_p^2$=.212), respectively.

In summary, for clinical symptom outcomes, the SOC group showed no significant change from baseline. In contrast, the PM group demonstrated statistically and clinically meaningful improvement across self- and other-reported symptom outcome measures (d ranging from 0.77 to 1.19) that exceeded changes in the SOC group (incremental d values ranging from 0.77 to 1.26; Table 4).

Figure 6 displays the NCI means over the study period and 95% confidence intervals for each group. Comparing the results at outset to those at completion revealed an improvement in the NCI from 92.0 ± 12.3 to 106.2 ± 8.1 in the PM group, whereas there was a decline in the SOC group from 96.9 ± 6.7 to 92.4 ± 24.2 (p<0.001). In turn, the GLM interaction term yielded a large and clinically important effect (${\eta }_p^2$=.260).

Composite memory scores over the study period are shown in Figure 7. The PM group improved by approximately one standard deviation (14.0 ± 11.4), whereas the SOC group declined by 5.4 ± 22.7 (p<0.001 with large and clinically meaningful effect size of ${\eta }_p^2$=.224).

Executive function scores (Figure 8) also showed an approximately one standard deviation improvement in the PM patients (16.9 ± 14.2), whereas there was little change in the SOC patients (1.8 ± 21.3). The GLM interaction term was significant (p=0.001) and yielded a large and clinically significant effect size (${\eta }_p^2$=.154).

The GLM model for processing speed indicated a significant group x time interaction (Figure 9), with the PM group improving from 103.5 ± 13.0 to 116.1 ± 15.7 points, whereas the SOC group improved more modestly, from 103.9 ± 11.9 to 106.4 ± 16.1 (p=0.010, ${\eta }_p^2$=.103). The CNS VS NCI and composite (memory and executive function) effects were both clinically meaningful and large in magnitude. Processing speed effect was also practically significant and medium-to-large in magnitude.

Supplemental Table S3 presents GLM models and change-from-baseline statistics for other CNS VS subtasks (beyond processing speed). GLM model interaction terms were significant for all subtests including verbal memory (p=0.020, ${\eta }_p^2$=.087), visual memory (p<0.001, ${\eta }_p^2$=.201), psychomotor speed (p=0.002, ${\eta }_p^2$=.145), reaction time (p=0.001, ${\eta }_p^2$=.155), complex attention (p=0.003, ${\eta }_p^2$=.139), cognitive flexibility (p<0.001, ${\eta }_p^2$=.171), simple attention (p=0.043, ${\eta }_p^2$=.066), and motor speed (p=0.018, ${\eta }_p^2$=.090), all of which showed significantly greater improvement in the PM group. These effects were both clinically significant and medium to large in magnitude. Supplemental Table S4 shows change-from-baseline statistics for each group on the CNS VS subtests. The PM group significantly improved from baseline on all subtests except for visual memory (p=0.061) and simple attention (p=0.115). The only significant change from baseline in the SOC group was visual memory, which declined by about 12 standard score points (p=0.024). Between-group comparison of change-from-baseline statistics indicated the PM group had significantly greater improvements on all subtests than the SOC group. These incremental effects were all clinically meaningful and ranged from medium to large magnitude (incremental d values ranging from 0.57 to 0.93).

The GLM interaction for the MoCA revealed only a trend that did not reach statistical significance (p=0.154, ${\eta }_p^2$=.032). While both groups’ MoCA performances significantly increased over the study period, there was a non-significant trend of greater improvement in the PM (3.8 ± 2.5 points) than SOC (2.6 ± 3.8 points) group by 0.41 SD units (95% CI, -0.11 to 0.92; Figure 10).

To summarize, the CNS VS primary outcome measures all significantly (p-values<0.001) and clinically meaningfully improved over the study period for the PM group (d ranging from 0.73 to 1.23) whereas there were no significant changes in the SOC group. Conversely, broad neurocognitive and composite memory performances declined from baseline in the SOC group. In turn, the PM improvements far exceeded SOC group changes (incremental d values ranging from 0.67 to 1.12; Table 4). Importantly, these CNS VS effects were virtually all large in magnitude. MoCA scores showed a weak trend favoring the PM group but the incremental effect of PM beyond SOC did not reach statistical significance.

Brain Training

Although BrainHQ was implemented as an intervention (for the PM group only), participants’ performance trajectories within the platform provided preliminary indicators of cognitive change over the course of the trial. All participants demonstrated improvement in their BrainHQ composite percentiles during the intervention period, with a mean increase of 19 percentile points (range: 3-29). Participants engaged with the training for an average of 52 hours across the study period (range: 15 minutes-164 hours).

The results also revealed a statistically and clinically significant group x timepoint interaction that approached large magnitude (p=0.011, ${\eta }_p^2$=.111). The PM group had greater improvement on the BrainHQ assessment composite by 0.75 SD units than the SOC group (95% CI, 0.17 to 1.32; Table 4 and Figure 11).

Biomarkers of AD

Blood-based biomarkers p-tau 217, GFAP, NfL, and Aβ42/40 ratio were evaluated prior to treatment and again at the completion of the trial (Table 5). Sixty-four of the 66 subjects had an abnormal Aβ42/40 ratio (<0.170) at baseline, and two had a normal ratio. Analysis of p-tau revealed that 25 subjects had normal p-tau 217 (<0.34ng/L) at baseline, whereas 41 did not: 21 were at a level that is strongly associated with amyloid accumulation (>0.63ng/L), 8 were at a level that is greater than 95% of amyloid-negative patients (0.48-0.63ng/L), and 12 were in the indeterminate range (0.34-0.47ng/L).

In the PM group, p-tau 217 declined modestly, whereas in the SOC group it increased slightly. Non-parametric within-group analyses revealed the PM group had a significant reduction in p-tau-217 from baseline (p=0.028, d=-0.71) whereas the SOC within-group reduction did not reach significance (p=0.234, d=-0.51). However, the magnitude of reduction in p-tau-217 between groups was not significant. That is, non-parametric comparison of the p-tau-217 change from baseline (Δ) between groups was statistically negligible (p=0.609, d=-0.13).

None of the changes in Aβ42/40 ratio, GFAP, or NfL reached statistical significance. There was a slight increase in Aβ42 in the PM group (baseline: 136.4 ± 161.3, follow-up: 139.7 ± 138.4), with a slight reduction in the SOC group (baseline: 169.3 ± 148.3, follow-up: 164.2 ± 143.3), but this was not significantly different. There was also a minimal decrease in GFAP in the PM group (baseline: 64.0 ± 29.8, follow-up: 57.5 ± 34.4), and minimal increase in the SOC group (baseline: 50.7 ± 23.9, follow-up: 51.5 ± 20.1), but these differences were not statistically significant.

Discussion

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