Aetna identifies a list of CPT, HCPCS and ICD-10 codes that are not covered when billed for the experimental indications described in this bulletin. Examples include procedural and device codes for CSF shunting and implanted neurostimulators (e.g., 62160, 62180-62258, 61863-61868, L8680-L8695), codes for immune globulin products and apheresis/plasma exchange (e.g., 36514, 36516, J1459, J1561–J1569, 90281–90283), fecal microbiota transplantation and related preparation codes (e.g., 0780T, 44705, G0455, J1440), selected drug injection codes (e.g., J0135, J1438, J1745), and the ICD-10 diagnosis codes for Alzheimer’s disease (G30.0–G30.9).

Providers should expect these listed codes to be treated as associated with experimental/investigational services for Alzheimer’s disease and therefore not covered when used for the interventions named in this policy (see code listings in the CPT/HCPCS/ICD-10 sections).

A randomized, double-blind, placebo-controlled trial of low-flow ventriculo-peritoneal CSF shunting in 215 subjects with probable Alzheimer’s disease was halted for futility after interim analysis; there were no between-group differences on the primary outcomes (Mattis Dementia Rating Scale and Global Deterioration Scale). The procedure was associated with increased adverse events, including 12 CNS infections, some temporally linked to CSF sampling, and the authors concluded there was no benefit to low-flow CSF shunting in mild-to-severe AD.

Systematic reviews and randomized trials of hormone replacement therapy (HRT/ERT) in postmenopausal women with dementia do not show consistent cognitive benefit. A Cochrane review (7 trials, 351 women) reported some measures worse with conjugated equine estrogens and limited, transient findings with low-dose preparations; the authors concluded that HRT/ERT is not indicated for cognitive improvement or maintenance in women with AD.

Based on the randomized sham‑controlled trial evidence, CSF shunting for Alzheimer’s disease is not supported. The RCT showed no cognitive or functional benefit and demonstrated an increased risk of central nervous system infections associated with the surgical procedure and study-related CSF sampling.

Multiple agents that reached randomized controlled testing failed to demonstrate clinically meaningful benefit and therefore are excluded from routine coverage. Examples include anti-amyloid antibodies and small molecules where pivotal trials were neutral (e.g., solanezumab), serotonin 5-HT antagonists (e.g., idalopirdine), histamine H3 receptor antagonists, and selective estrogen receptor modulators (e.g., raloxifene); the aggregated trial data do not support routine medical necessity for these interventions.

In a large, randomized, double-blind, placebo‑controlled 78‑week study of the BACE‑1 inhibitor verubecestat (n=1,958 randomized), the trial was terminated early for futility. There were no significant differences versus placebo on the co‑primary outcomes (ADAS‑cog and ADCS‑ADL) and adverse events (including rash, falls, sleep disturbance, weight loss and suicidal ideation) were more common in the active arms; these results do not support clinical use of verubecestat for mild‑to‑moderate AD.

A phase II randomized study of crenezumab (n=431) did not meet its primary or secondary endpoints. An exploratory post‑hoc signal favoring higher‑dose treatment in a milder subset (MMSE 22–26) was observed, but overall results were insufficient to establish efficacy for routine clinical use and support only further study at higher doses in earlier disease.

Sections of the bulletin summarize background and trial-level evidence for numerous investigational therapies (for example, γ‑secretase inhibitors, monoclonal antibodies, intranasal insulin, IVIG, and neuromodulation), but these narrative segments do not themselves state discrete coverage determinations. They are presented as evidence summaries to inform clinical judgment and policy decisions rather than as standalone coverage rules.

Interpretation of the evidence is limited by heterogeneity across studies, including small numbers of trials for many interventions, variable subject characteristics (age, disease severity, biomarker selection), differing outcome measures and follow‑up durations, and varied intervention protocols. These methodological differences restrict the ability to draw broad conclusions about efficacy for several experimental therapies.

The bulletin’s additional information pages provide administrative material, external links, and a copyright/disclaimer statement. These sections do not add new coverage exclusions for clinical interventions; they include standard disclaimers that Clinical Policy Bulletins are informational and do not constitute an offer of coverage or medical advice.

The bulletin’s primary coverage stance is that the enumerated treatments (items 1–65) are considered experimental/investigational for Alzheimer’s disease because their effectiveness for this indication has not been established; as such, these interventions are treated as not medically necessary for routine clinical care outside approved research protocols.

Examples across multiple trial programs illustrate the policy rationale: semagacestat worsened functional outcomes and increased adverse events; large simvastatin and other statin trials showed no cognitive benefit; low‑flow CSF shunting was futile and associated with infections; and monoclonal antibody programs (for example, bapineuzumab, solanezumab, and verubecestat) failed to demonstrate consistent clinical efficacy in pivotal trials—findings that support the investigational and noncoverage posture for these therapies.

Bapineuzumab and solanezumab produced biomarker effects in some studies but did not translate into statistically significant improvements on primary clinical endpoints in phase III trials; safety considerations (for example, ARIA and vasogenic edema) further complicate their clinical use outside trials.

The policy urges avoidance of routine clinical use for agents lacking positive pivotal evidence—citing solanezumab, idalopirdine, H3 antagonists, and raloxifene among others—as these therapies have not shown reliable cognitive or functional benefit in randomized controlled studies.

Specific negative findings reported include no significant ADAS‑Cog differences for raloxifene at 12 months, no functional benefit for adding 2 years of home‑based occupational therapy to collaborative care, and no proof‑of‑concept for edonerpic maleate at tested doses—supporting their experimental classification.

Edonerpic maleate phase II results (safety population n=482) showed ADAS‑Cog mean changes at 52 weeks that were not significantly different from placebo and higher discontinuation for adverse events in active groups, leading to the conclusion that clinical proof‑of‑concept was not demonstrated.

The document does not convert each narrative evidence summary into a separate formal 'not medically necessary' statement within the cited chunks; instead, it consistently frames the interventions as investigational and highlights the need for further high‑quality randomized data to support routine coverage.

The CODING section aggregates the experimental/not‑covered codes into a single code group for administrative use. The listed codes include procedural, device, infusion, drug and ICD‑10 diagnosis codes that correspond to many of the interventions identified as experimental in this policy and are referenced for claims processing.

Supplementary administrative pages included with the bulletin provide policy history, links to the glossary and other resources, and a copyright/disclaimer statement; these pages do not introduce new clinical coverage exclusions and reiterate that the CPB is informational and subject to change.