I've spent the last several months doing deep research into what can actually be done for my mother (74F, MCI due to AD, CDR 0.5, MMSE 28-30). She also has cerebral amyloid angiopathy (CAA), which means she can't take any of the anti-amyloid antibody drugs (lecanemab, donanemab) and is excluded from most clinical trials because of her MRI findings (microbleeds and superficial siderosis). So I had to look beyond the headline drugs and trials and find everything else with real evidence behind it.

This isn't medical advice. I'm not a doctor. But I've read the trials, talked to specialists at Brigham and Women's, MGH, and Yale, and built a protocol with their input. I'm sharing it because I wish someone had handed me this list when we got the diagnosis.

One important note: Because my mother has CAA (cerebral amyloid angiopathy) with microbleeds and superficial siderosis, everything in this protocol has been filtered for bleed safety. That means I may have excluded interventions that are perfectly appropriate for someone without CAA. If your loved one doesn't have CAA or cerebrovascular disease, there may be additional options available to them that I haven't included here. Always check with their neurologist.

Everything below is something you can do without a clinical trial, most of it without a prescription, and all of it with published evidence in humans (not just mice). Organized roughly by impact.

Disease modification vs symptom treatment: Most Alzheimer's drugs just treat symptoms. They might improve cognition temporarily but the disease keeps progressing underneath. Disease modification means actually slowing or stopping the underlying pathology: amyloid accumulation, tau spreading, neuroinflammation, brain atrophy. That's what this list focuses on. I've tried to be honest about which interventions have disease-modifying evidence (biomarker changes, atrophy reduction, slowed conversion to dementia) vs which ones just improve symptoms or have only mechanistic rationale. Both matter, but they're not the same thing.

TIER 1: The non-negotiables

1. Fix their hearing

This might be the most important thing on this list. The Lancet Commission ranks hearing loss as the #1 modifiable risk factor for dementia (~8% of attributable risk). The ACHIEVE trial (2023) showed hearing aids slowed cognitive decline by 48% in at-risk older adults over 3 years.

Why: when the brain is working overtime to hear, it's stealing processing power from memory and cognition. That tax compounds every day. A 48% reduction in the rate of cognitive decline over 3 years is disease-modifying-level impact. The Lancet Commission also cites evidence that untreated hearing loss is associated with accelerated brain atrophy, particularly in the temporal lobe.

What to do: Get an audiogram. If there's any hearing loss, get hearing aids. Costco is the best value - $1,499-1,699 per pair for the same technology that costs $4,000-6,000 at private audiologists. Get rechargeable ones with Bluetooth so they can stream music (see below). Don't let them say "my hearing is fine" - high-frequency hearing loss is invisible to the person experiencing it. They're missing consonant sounds and compensating without realizing it.

2. Test and treat sleep apnea

Untreated sleep apnea may be one of the most damaging things that can happen to an Alzheimer's brain. During deep sleep, the glymphatic system clears amyloid and metabolic waste from the brain. Sleep apnea disrupts deep sleep and causes intermittent oxygen deprivation. Years of untreated apnea means years of impaired amyloid clearance.

What to do: Get a sleep study. If they had one years ago and were told it resolved, retest. If they have apnea, CPAP compliance is critical - this is not optional. Even mild untreated apnea accelerates amyloid accumulation.

The disease-modifying case: longitudinal PET imaging studies show that people with untreated sleep apnea have significantly faster amyloid accumulation over time compared to controls. CPAP treatment in the ADNI cohort was associated with slower cognitive decline and delayed age of MCI onset by approximately 10 years. Intermittent hypoxia also damages cerebral microvasculature, which is directly relevant to anyone with or at risk for CAA.

3. Aerobic exercise - 150-300 minutes per week

Consistently one of the strongest interventions in the literature. Exercise increases BDNF (brain-derived neurotrophic factor), improves blood flow to the brain, and reduces neuroinflammation. It doesn't need to be intense. Steady moderate exercise (walking, stationary bike, swimming) beats occasional hard workouts.

The disease-modifying case: the FINGER trial included aerobic exercise as a core component and showed sustained cognitive benefit. Multiple imaging studies show that aerobic exercise slows hippocampal atrophy in MCI patients. Erickson et al. (2011, PNAS) showed that 1 year of aerobic exercise actually increased hippocampal volume by 2%, effectively reversing 1-2 years of age-related loss. The ADEX trial showed 16 weeks of moderate-to-high intensity exercise reduced neuropsychiatric symptoms and showed trends toward slower cognitive decline in AD patients. Exercise also reduces neuroinflammation (measured by reduced inflammatory cytokines in CSF) and improves cerebrovascular function, which directly affects amyloid clearance. This is as close to proven disease modification as any non-drug intervention gets.

What to do: 30 minutes of moderate aerobic exercise, 5-7 days a week. A stationary recumbent bike is ideal for people with balance issues. Walking counts. The key is consistency - every day matters more than any single session.

If they have CAA or are on blood thinners: avoid anything with fall risk. A fall causing a head impact in someone with cerebral microbleeds could be catastrophic. Stationary equipment is safer than outdoor walking on uneven surfaces.

4. Strength training - 2x per week

The SMART trial (Mavros 2017, JAMA) is the big one here. High-intensity progressive resistance training (80% of 1-rep max, 2x/week for 6 months) significantly improved cognition in MCI patients, and the gains were still there at 18-month follow-up. The cognitive improvement correlated directly with strength gains. The more they got stronger, the more their cognition improved. The mechanism is likely BDNF release, which requires high enough intensity to trigger it.

This means strength training isn't just maintenance. At the right intensity, it's a disease modifier.

What to do: Sit-to-stand from a chair (no hands), wall pushups, light dumbbell work (5-10 lbs), heel raises, tandem stance holds for balance. 2 sessions per week. Keep it functional. If your loved one does NOT have CAA or cerebral microbleeds, talk to their doctor about progressive overload toward heavier resistance. That's where the strongest cognitive data is.

Important for CAA patients: No heavy lifting, no breath-holding during exertion (Valsalva maneuver), no planks or sustained isometric holds that work muscles (wall sits, plank holds, static squat holds, etc.). Isometric contractions cause progressive blood pressure elevation throughout the hold. Sustained contraction can push systolic BP dangerously high, which is exactly what you need to avoid with cerebral microbleeds. Keep breathing, keep moving, never strain to failure. Cap weights at ~10 lbs without neurologist clearance. Balance holds (like tandem stance) are fine. Those are neurological training, not muscle loading. The unfortunate reality is that the intensity level that produced the strongest cognitive results in SMART is the intensity level that's unsafe with CAA. Lighter work is still valuable for balance, function, and fall prevention, but probably doesn't hit the BDNF threshold that made SMART so impressive.

5. Blood pressure management

This is especially critical if they have any cerebrovascular disease or CAA, but it matters for all AD patients. It's not just average BP that matters. Spikes from stress, exertion, or straining are a risk factor for hemorrhage on their own.

The disease-modifying case: SPRINT-MIND (2019, JAMA) showed that intensive systolic BP control (<120 mmHg) significantly reduced the risk of MCI and slowed white matter lesion progression on MRI. Observational data from ADNI shows that midlife hypertension is associated with greater amyloid deposition on PET. BP management doesn't just prevent strokes. It directly affects the rate of AD pathology accumulation.

What to do: Buy a home BP monitor. Log readings 2-3x daily for at least a week. Bring the log to your doctor. Target generally is <130 systolic for most AD patients, but ask your neurologist for a specific target. Avoid high-sodium foods. Manage constipation (straining causes BP spikes). If they're on BP medication, make sure it's not dropping them too low - orthostatic hypotension (dizziness on standing) is a major fall risk.

TIER 2: Fixable cognitive drains

6. Treat chronic pain and systemic inflammation (especially arthritis)

Untreated chronic pain from arthritis isn't just a comfort issue. It drives systemic inflammation, limits exercise capacity, increases fall risk, and wrecks sleep. All of those make cognition worse. Chronic inflammation sends pro-inflammatory cytokines (IL-6, TNF-alpha, CRP) across the blood-brain barrier, where they directly accelerate neuroinflammation, amyloid deposition, and tau pathology.

The disease-modifying case: elevated midlife CRP and IL-6 predict faster amyloid accumulation on PET imaging decades later (Walker et al., JAMA Neurology 2019). Chronic systemic inflammation isn't just correlated with AD. It's on the causal pathway. Managing pain removes a direct accelerant of the underlying disease, and it unlocks exercise, which is one of the strongest disease modifiers on this list. Force multiplier.

What to do: If they have arthritis, get it managed. Acetaminophen (Tylenol) is first-line and has no bleeding risk. Topical diclofenac (Voltaren cream, available OTC) has low systemic absorption and is reasonable. Intra-articular corticosteroid or hyaluronic acid injections are local only with no systemic bleeding risk. Physical therapy for joint-specific strengthening reduces pain and improves stability.

What to avoid: Oral NSAIDs (ibuprofen, naproxen, meloxicam) increase bleeding risk, especially dangerous if they have CAA or cerebral microbleeds. Occasional use for severe pain may be acceptable per your neurologist, but avoid chronic daily use. Opioids increase fall risk, cause sedation, and worsen cognition. Avoid entirely if possible.

The broader point: any source of chronic inflammation - untreated dental disease, chronic infections, poorly managed autoimmune conditions - is feeding the fire in their brain. Don't ignore this stuff.

7. Medication audit - kill the anticholinergics

Acetylcholine is already depleted in Alzheimer's brains. A shocking number of common medications actively block what's left. Diphenhydramine (Benadryl, ZzzQuil, many OTC sleep aids and allergy meds), many bladder medications (oxybutynin, solifenacin), some older antidepressants. The cognitive hit from these drugs in someone with AD is real, and often reversible just by stopping them.

The disease-modifying case: a large prospective study (Gray et al., JAMA Internal Medicine 2015) followed 3,434 older adults for over 7 years and found that cumulative anticholinergic use was associated with a dose-dependent increase in dementia risk. Higher anticholinergic exposure correlated with greater brain atrophy and lower glucose metabolism on PET. This isn't just masking symptoms. These drugs are accelerating the structural damage.

What to do: Go through every medication and supplement with a pharmacist or doctor. Use the Beers Criteria or the ACB (Anticholinergic Cognitive Burden) scale to check each one. Eliminate anything anticholinergic that isn't absolutely necessary.

Also relevant: If they're on an SSRI (fluoxetine, sertraline, etc.) and also have CAA or cerebral microbleeds, know that SSRIs have antiplatelet effects that increase bleed risk. This doesn't mean stop immediately - talk to their neurologist - but it should be reviewed. Fluoxetine is one of the worst offenders. If an antidepressant is needed, bupropion (Wellbutrin) or mirtazapine (Remeron) have no antiplatelet mechanism.

8. Deep sleep optimization

Beyond treating apnea, a bunch of common things wreck the deep sleep your loved one's brain needs for amyloid clearance. A suvorexant study (Science Translational Medicine 2023) showed that enhancing deep sleep with a dual orexin receptor antagonist reduced CSF amyloid-beta and phosphorylated tau in humans. That's direct disease-modifying evidence that sleep quality changes the actual pathology, not just symptoms.

What to do:

• Stop Ambien/zolpidem if they're taking it - it suppresses deep sleep architecture
• Know that many SSRIs (especially fluoxetine) suppress deep sleep and REM sleep - another reason to review whether the antidepressant they're on is still the right one
• Consistent sleep schedule (same bedtime, same wake time)
• Cool, dark room
• No alcohol (suppresses deep sleep)
• Limit blue light before bed
• Consider pink noise during sleep - there's evidence it enhances slow-wave (deep) sleep
• Consider melatonin sustained-release (see supplements below)

TIER 3: Supplements with actual human evidence

I'm not including anything that only has mouse data. Everything here has published results from human trials.

9. Melatonin (sustained-release) - 3-6mg at bedtime

Not just a sleep aid. A 2025 meta-analysis (Alzheimer's Research & Therapy, 8 RCTs, n=518) showed significant cognitive improvement overall, with the strongest effect in MCI patients (MD 2.63, p<0.000001) over 13-24 weeks. The Cardinali group showed MCI patients on melatonin 3-24mg over 15-60 months had significantly better MMSE and ADAS-Cog scores vs controls.

Get sustained-release, not immediate-release. The brain benefits come from sustained overnight exposure, not a quick pulse. We use Pure Encapsulations Melatonin-SR, which matters because OTC melatonin content varies wildly across brands (tested ranges from -83% to +478% of what's on the label, which is insane). Start at 3mg, can go to 6mg after 2-4 weeks.

One caveat: the human trials so far measured cognitive scores, not PET biomarkers. But the Cardinali group's long-term data (15-60 months) showed MCI patients on melatonin had significantly slower progression to dementia vs controls. Slowing conversion from MCI to dementia is a disease-modifying outcome, not just symptom management. Mechanistically, melatonin is anti-amyloidogenic and enhances glymphatic clearance via AQP4 polarization. A University of Iowa trial is currently the first to test blood biomarker endpoints.

10. Benfotiamine - 300mg twice daily

This is a fat-soluble form of vitamin B1 (thiamine) with ~5x the bioavailability of regular thiamine. The BEACON trial (Gibson et al., Phase IIa, N=70, 12 months): 77% less CDR worsening (p=0.034), 43% less ADAS-Cog decline. The MMSE ≥26 subgroup (mild impairment) showed significant cognitive benefit (p=0.027). APOE non-E4 carriers responded more strongly.

There's a larger confirmatory trial (BenfoTeam, N=406, ADCS) currently running. The biological rationale is solid - thiamine-dependent enzymes are documented to be reduced in AD brains, and benfotiamine corrects glucose metabolism dysfunction.

No significant adverse events in any trial. Take with meals. This is essentially a vitamin at a higher dose.

11. Lithium orotate - 5-20mg daily

This one requires a longer explanation because it's controversial and the evidence is complicated.

The background: Lithium has been used psychiatrically for decades at high doses (600-1800mg lithium carbonate). At those doses it requires blood monitoring for toxicity. Lithium orotate delivers elemental lithium at a fraction of that dose - 20mg orotate = ~1mg elemental lithium, vs 113-340mg elemental from psychiatric dosing.

The evidence:

• Yankner/Harvard (Nature 2025): First demonstration that lithium naturally exists in brain tissue. Orotate at micro-doses nearly completely prevented plaque formation and tau phosphorylation in AD mice, and reversed cognitive impairment when started after pathology was established. Carbonate barely differed from placebo.
• Denmark 2017: Lower dementia rates in regions with higher lithium in drinking water
• UK 2022: Lithium-prescribed patients ~50% less likely to develop dementia
• LATTICE 2025 (Pittsburgh): 80 MCI patients, 2 years lithium carbonate, roughly halved the rate of verbal memory decline
• Forlenza 2019 (Brazil): 61 MCI patients, 2 years, slowed MCI-to-dementia conversion

The mechanism: Lithium inhibits GSK-3β, a kinase that drives tau phosphorylation and amyloid processing. If your loved one has elevated p-tau, this is directly targeting their active pathology.

At 5-20mg orotate, you're well below any toxicity threshold. Recheck kidney function (creatinine, eGFR) at 1-3 months as a precaution. Monitor thyroid if they're on levothyroxine. If they're on an SSRI, start at 5mg and go slow - or wait until the SSRI is tapered.

Caveat: No human RCT has been done on lithium orotate specifically. The Yankner mouse data is striking but unconfirmed in humans. A clinical trial at Mass General/Brigham is expected in 2026.

TIER 4: Lifestyle interventions with strong evidence

12. 40Hz gamma stimulation (light + sound)

This is the Cognito Therapeutics approach - flickering light and pulsing sound at exactly 40Hz to entrain gamma oscillations in the brain. In mouse models, this dramatically reduced amyloid and tau. The OVERTURE trial in humans showed modest but real slowing of hippocampal atrophy.

The clinical device isn't available yet (pending FDA clearance), but you can approximate it at home: 40Hz flicker video on a screen + 40Hz binaural or isochronic audio through headphones. Ideally the light and sound should be synchronized. The brain entrains more effectively when both stimuli are phase-locked at the same frequency. Some apps (like AlzLife) attempt to do this. If you're using separate light and sound sources, getting them to start at the exact same time is the best you can do. Do it during something mentally engaging (crossword, puzzle, learning something new) for ~1 hour daily. There's some evidence that gamma entrainment + cognitive effort at the same time works better than either alone.

Upcoming readouts to watch: MIT GENUS (April 2026) and Cognito HOPE trial (June 2026).

13. Cognitive engagement - effortful learning, not puzzles

Word searches and Sudoku have weak evidence. What actually works is learning something new and hard. Stuff that forces the brain to build new circuits. A new language (Duolingo with real practice). A musical instrument. A demanding course in history or literature, anything that requires retention and synthesis. If it feels easy, it's not doing much.

The disease-modifying case: the FINGER trial (2015, Lancet) tested a multi-domain intervention that included intensive cognitive training alongside exercise, diet, and vascular management. The cognitive training group showed significantly better cognitive performance AND the benefit was sustained at extended follow-up. Cognitive reserve theory is also backed by imaging data. People with more lifetime cognitive activity show less brain atrophy per unit of amyloid burden, meaning the same amount of pathology causes less clinical damage. You're literally building a buffer.

14. Social engagement - minimum 4-5x per week

Isolation accelerates cognitive decline faster than almost any biological risk factor. This isn't soft advice. It's one of the most replicated findings in the field. Regular meaningful social contact means structured activities: classes, groups, outings with friends. Not just sitting in the same room as family with the TV on.

The disease-modifying case: the Lancet Commission identifies social isolation as a modifiable risk factor for dementia. Longitudinal imaging studies show that socially isolated older adults have faster hippocampal atrophy and greater amyloid burden than socially engaged controls. The FINGER trial included social engagement as part of its multi-domain intervention that produced sustained cognitive benefit. Chronic isolation also elevates cortisol, which is directly neurotoxic to the hippocampus and accelerates tau phosphorylation.

If you're relocating your loved one, plan social activities before the move, not after. The transition period is when isolation hits hardest.

TIER 5: Things to discuss with their doctor

15. Liraglutide (injectable GLP-1 agonist)

The ELAD trial (Nature Medicine, December 2025) showed 50% reduction in brain atrophy and 18% slower cognitive decline over 12 months with liraglutide (Victoza). This is an injectable GLP-1 originally approved for diabetes. It requires a prescription and is used off-label for neuroprotection. Standard titration: 0.6mg → 1.2mg → 1.8mg daily over 2-3 weeks.

Important: If your loved one has had weight loss or low BMI, monitor carefully - GLP-1s can cause further weight loss. Also: oral semaglutide (Ozempic in pill form) failed two AD trials in late 2025. The injectable route has better brain penetration. Liraglutide specifically is the one with positive data, not semaglutide.

16. Sleep study and CPAP (mentioned above but worth repeating - requires a doctor's order)

17. Physical therapy for balance and fall prevention - especially critical if they have CAA or any cerebrovascular disease. A PT can assess whether they need an assistive device and build a fall prevention program.

What I'm NOT including (and why)

• Lecanemab/donanemab: Require infusion centers, extensive monitoring, and carry ARIA risk (brain swelling/bleeding). Also only available if your MRI is clean enough. If your loved one qualifies, talk to their neurologist. But this post is about what you can do on your own.
• Commercial brain training apps: Mostly weak evidence. Real-world effortful learning is better supported.
• Coconut oil / MCT oil: The "Type 3 diabetes" hypothesis has some biological plausibility but the evidence for coconut oil in humans is basically anecdotal.
• Anything with only mouse data and no human trials: There's a ton of exciting preclinical stuff. I'm only including things that have been tested in actual humans.
• High-dose vitamin E: The TEAM-AD trial showed modest benefit in moderate AD but there's also data showing increased mortality risk in other contexts. Not worth it.

None of this is going to cure Alzheimer's. But the research consistently shows that stacking interventions ex. vascular control + exercise + hearing correction + sleep + social engagement + the right supplements - can slow things down.

If you're also looking at clinical trials, I've spent months mapping the landscape for someone with complicated MRI findings who can't do the standard anti-amyloid drugs. Happy to share what I've learned about tau-targeting trials, zervimesine, BIIB080, and how to navigate the trial system if people are interested.

Note: removed a few things, now only 17.