The Science Behind the Mission
Understanding Alzheimer's
Before It Begins
The TOMMORROW study established that prevention is possible — if we understand the science early enough. Explore the genetics, detection methods, and strategies that define the frontier of Alzheimer's research.
with Alzheimer's today
biological changes begin
influenced by lifestyle
Primary Risk Marker
The APOE Gene
The APOE geneApolipoprotein E — a gene with three common variants (e2, e3, e4). The e4 variant is the strongest known genetic risk factor for late-onset Alzheimer's, influencing how the brain clears amyloid protein. produces a protein that transports cholesterol in the brain. Its three variants carry dramatically different risk profiles. Select a genotype below to explore what the research shows.
Select an APOE genotype:
The Study's Namesake
The TOMM40 Gene
TOMM40 — Translocase of the Outer Mitochondrial Membrane 40 — is the direct scientific namesake of the TOMMORROW study. Located adjacent to APOE on chromosome 19, it encodes a protein critical to mitochondrial energy regulation in neurons.
A poly-T repeat within TOMM40 (rs10524523) offers a finer-grained prediction tool. "Very Long" repeat lengths are associated with earlier onset of MCIMild Cognitive Impairment — the earliest clinically detectable stage of cognitive decline. MCI does not significantly impair daily life but carries meaningful risk of progression to Alzheimer's dementia. in APOE e3 carriers — making individualized prevention timelines scientifically plausible for the first time.
Neurons are among the most energy-demanding cells in the body. When TOMM40 function is impaired, proteins that should enter mitochondria accumulate outside them — triggering cellular stress, inflammation, and neuronal death. This is a distinct pathway from amyloid, making TOMM40 a separate and potentially earlier therapeutic target.
TOMM40 poly-T analysis is not yet part of standard clinical testing. It has been used in research settings — including the TOMMORROW trial — and several academic medical centers offer it through research programs. Speak with a genetic counselor to explore research participation that includes this analysis.
A Landmark in Predictive Genetics
The TOMMORROW study combined APOE and TOMM40 analysis to build a Biomarker Risk AlgorithmA validated statistical model combining genetic markers to estimate the probability and timing of MCI onset in cognitively healthy individuals. — one of the first validated attempts to predict MCI onset age in healthy adults before any symptoms appeared. Recognized by Emory University's Alzheimer's Disease Research Center, it marked a turning point: prevention was no longer theoretical. The TOMMORROW study gave researchers a window, and this collective was built to keep it open.
Beyond Single Genes
Polygenic Risk & What It Means for You
APOE and TOMM40 are the most studied markers, but Alzheimer's risk is polygenic. A Polygenic Risk ScoreA numerical score aggregating the effects of hundreds of genetic variants, each contributing a small amount to overall risk. PRS provides a more comprehensive picture than single-gene testing. (PRS) combines effects from hundreds of variants — including CLU, BIN1, PICALM, and SORL1 — to produce a composite estimate. PRS combined with lifestyle and biomarker data may eventually power individualized prevention protocols.
PRS models incorporate variants from GWAS studies analyzing over one million individuals. Key non-APOE variants include CLU (amyloid clearance), BIN1 (tau pathology), PICALM (amyloid transport), and CR1 (neuroinflammation) — each contributing a small but measurable effect to overall risk.
No. A PRS describes probability, not destiny. Many with high scores never develop Alzheimer's; some with low scores do. Risk scores are most powerful as tools for research enrollment and motivating prevention behaviors — not as definitive diagnoses. Genetic counseling is strongly recommended.
The Clinical Threshold
What Is MCI?
Mild Cognitive ImpairmentCognitive decline greater than expected for age and education, but not severe enough to interfere with daily activities. MCI is the earliest detectable clinical stage on the Alzheimer's continuum. sits at the boundary between normal aging and early Alzheimer's dementia. People with MCI notice memory slips, word-finding difficulty, or subtle reasoning changes — but retain full independence in daily life.
Approximately 15–20% of adults over 65 have MCI. Of these, 10–15% per year progress to Alzheimer's dementia — vs. 1–2% of cognitively healthy adults. The TOMMORROW study was built to target this window.
Normal aging involves gradual slowing that does not significantly worsen over time. MCI is distinguished by measurable decline on standardized tests — typically 1.5 standard deviations below age-adjusted norms — and a pattern that worsens over serial assessments. Forgetting where you put your keys is normal aging; forgetting what keys are for may signal something more.
In some cases, yes. MCI caused by depression, sleep apnea, thyroid dysfunction, or vitamin deficiencies can improve with treatment. Even for MCI on the Alzheimer's continuum, lifestyle interventions can slow progression — which is why early identification matters so much.
The Diagnostic Toolkit
Biomarkers in Practice
Modern Alzheimer's research relies on a suite of biomarkersBiological indicators that can be objectively measured to signal normal or abnormal processes. Key Alzheimer's biomarkers include amyloid and tau protein levels detectable via CSF or PET imaging. to detect disease years or decades before symptoms appear. Click each to explore.
Amyloid PET uses a radioactive tracer binding to amyloid plaques. A positive scan can precede cognitive symptoms by 10–20 years. FDA approval of lecanemab and donanemab has expanded its clinical use — a positive scan now directly informs treatment eligibility.
CSF analysis measures tau and phospho-tau with high sensitivity. Elevated p-tau217 is specific to Alzheimer's pathology. A lumbar puncture is required — invasive but highly accurate, and often used to confirm PET findings in clinical trials.
Plasma p-tau217 and the Abeta42/40 ratio identify Alzheimer's pathology with accuracy rivaling CSF and PET — at a fraction of the cost. These tests are becoming available through specialty centers and are expected to transform population-level screening within this decade.
Standardized batteries — including the ADAS-Cog, MoCA, and the TOMMORROW neuropsychological protocol — measure memory, attention, language, and executive function. Serial testing over time is more informative than any single snapshot, capturing the trajectory that distinguishes disease from normal variance.
How Prevention Trials Are Designed
From Enrollment to Endpoint
Phase 1 — Screening and Risk Stratification
Participants undergo APOE/TOMM40 genotyping, a neuropsychological baseline assessment, and biomarker profiling. Eligibility is defined by risk-stratification algorithms like the TOMMORROW approach — identifying cognitively healthy adults statistically likely to develop MCI within a defined window.
Phase 2 — Randomization
High-risk participants are randomized double-blind to drug or placebo. Cognitive testing is administered every six months measuring executive functionCognitive processes including working memory, flexible thinking, and self-control. Executive function deficits are among the earliest detectable signs of Alzheimer's-related cognitive change. and episodic memory.
Phase 3 — Longitudinal Biomarker Monitoring
Biomarkers are reassessed annually. Amyloid PET or CSF sampling confirms whether the agent is engaging its target — distinguishing symptomatic benefit from true disease modification.
Primary Endpoint
For prevention trials, the gold standard is a significant delay in MCI diagnosis measured relative to predicted onset from the baseline risk algorithm. A drug delaying onset by two years compresses the disease's total burden significantly at a population level.
Lifestyle Interventions
The Evidence-Based Foundation
Evidence from the FINGER trial and WHO guidelines establishes that modifiable lifestyle factors can meaningfully reduce dementia risk. These are not cure claims. They represent risk reductionA statistical decrease in the probability of developing a disease, measured against an untreated control group. Risk reduction shifts the probability favorably without guaranteeing prevention. with real clinical significance. Select any card to learn more.
The Research Pipeline
Investigational Drug Landscape
Alzheimer's drug development has shifted decisively toward prevention and early intervention — the precise approach pioneered by the TOMMORROW study. Click any row to expand details.
| Agent | Mechanism | Target Stage | Phase |
|---|---|---|---|
| Lecanemab | Anti-amyloid monoclonal antibody targeting protofibrils | Early / MCI | Approved |
| Lecanemab (Leqembi) received full FDA approval in 2023 based on the CLARITY AD trial, showing 27% slowing of clinical decline over 18 months. Administered intravenously every two weeks, it requires amyloid PET or CSF confirmation for eligibility — and its approval validated the amyloid hypothesis for disease-modifying therapy. | |||
| Donanemab | Anti-amyloid antibody targeting N3pG-Abeta plaques | Early Symptomatic | Approved |
| Donanemab (Kisunla) received FDA approval in 2024, showing 35% slowing of decline in the TRAILBLAZER-ALZ 2 trial. Uniquely, treatment stops after plaque clearance is confirmed — making it the first Alzheimer's therapy designed with a defined endpoint rather than indefinite dosing. | |||
| Semaglutide (AD trials) | GLP-1 receptor agonist; neuroprotective and anti-inflammatory | Pre-symptomatic | Phase III |
| Semaglutide is in Phase III prevention trials, driven by observational data showing lower dementia rates in GLP-1 agonist users. Proposed mechanisms include reduced neuroinflammation and improved brain insulin signaling. EVOKE and EVOKE PLUS trial results are anticipated by 2027. | |||
| Tau Vaccines | Active immunotherapy targeting tau protein aggregation | Pre-clinical / MCI | Phase II |
| Tau pathology correlates most closely with cognitive decline and remains a major frontier beyond amyloid. Active tau vaccines train the immune system to clear pathological tau. ACI-35.030 and AADvac1 are the most advanced candidates, showing early tolerability and immunogenicity. | |||
| APOE4 Modulators | Gene-targeted therapy reducing APOE4 neurotoxicity | Genetic High-Risk | Phase I/II |
| APOE4 modulators aim to convert the APOE4 protein to behave like the benign APOE3 variant using antisense oligonucleotides. These are the most genetically targeted approach in the pipeline — most directly relevant to individuals identified as high-risk through the TOMMORROW biomarker algorithm. | |||
Primary Literature & Key Studies
Research Deep-Dive
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