What is PCAD?

Preclinical Alzheimer’s Disease (PCAD) is a state in which a patient tests as cognitively normal, but pathology indicative of Alzheimer’s disease is present. Abnormal concentrations of the amyloid protein in the brain are the defining characteristic of PCAD, according to the Alzheimer’s Association, although some level of neurodegeneration may also be present. Currently, the U.S. Food and Drug Administration defines the condition as a stage of  “characteristic pathophysiological changes of Alzheimer’s disease but no evidence of clini­cal impact.”  PCAD can be differentiated from genetically-determined causes of Alzheimer’s disease , including early onset Alzheimer’s disease, and which have been termed “Stage Zero” of the disease.  

PCAD Prevalence

Ongoing research suggests that abnormal brain amyloid concentration among U.S. adults is a highly prevalent condition: as many as 22 percent of U.S. adults according to a 2019 systematic review and meta-analysis. Subsequent clinical trials utilizing blood biomarker measurement suggest that nearly 6 percent of adults aged over 50 years have a high level of amyloid concentration that is indicative of short or mid-term progression to symptomatic Alzheimer’s disease, (i.e. patients testing in the highest tertile on p-tau217 concentrations indicative of amyloid.) This high-risk population has been estimated to number over 7 million adults over the age of 50, (5.8 percent of 2023 US adult population).   

By comparison, recent estimates of the U.S. population with early symptomatic Alzheimer’s disease – the stages at which treatment with disease modifying therapy may be appropriate – are in the range of 666,000 adults with mild cognitive impairment due to Alzheimer’s disease, and 620,000 adults with mild dementia due to Alzheimer’s disease.  

PCAD and Progression to Early Symptomatic Alzheimer’s Disease  
As noted above, recent research suggests that patients who test as cognitively normal, but who have relatively high levels of amyloid concentration in the brain are at high risk for progression into early stages of Alzheimer’s disease, including mild cognitive impairment or mild dementia. Findings from clinical trials on potential disease-modifying treatment of PCAD indicate that upwards of 50 percent of individuals in the top tertile for “amyloid positivity”, (top tertile of amyloid concentration measured by p-Tau217 blood biomarker tests) will progress to symptomatic disease within 4.5 years, a level of risk four times that of individuals without elevated amyloid levels. Recent studies also strengthen findings that the risk of progression from pre-clinical to symptomatic Alzheimer’s disease increases markedly with age.  

Asymptomatic individuals aged 40-60 who carry one or two copies of the epsilon-4 allele of the apolipoprotein E (APOE) gene are also at elevated risk for progression to symptomatic disease.  About 25 percent of  the U.S. population is thought to carry one copy of APOE4, and 2 to 3 percent carry two copies.    Other genetic variations are responsible for high risks of early onset Alzheimer’s disease (i.e. disease occurring before age 60, accounting for about 1-2 percent of all AD cases), and for the extremely high prevalence of Alzheimer’s disease among individuals with Down syndrome.

How is PCAD detected?

PCAD can be detected by conventional diagnostics that are capable of identifying amyloid concentrations in the brain, such as PET imaging and cerebrospinal fluid (CSF) analysis. However amyloid-PET imaging and CSF analysis are intrusive processes that ordinarily would not be ordered for a patient showing no signs of Alzheimer’s disease or other forms of dementia. Blood biomarker testing is a minimally intrusive (administered by blood draw) process. New and emerging blood biomarker tests are demonstrating accuracy on a par with conventional diagnostics.  In 2025 the Alzheimer’s Association issued a first-ever clinical practice guideline on use of blood biomarker testing in specialty care.

Is PCAD a treatable condition?

Anti-amyloid disease-modifying therapies are approved by the U.S. Food and Drug Administration for treatment of early, symptomatic Alzheimer’s disease, (mild cognitive impairment or mild dementia due to Alzheimer’s disease), but not for treatment of PCAD. Late stage clinical trials are testing the safety and effectiveness of disease modifying therapies for treatment of PCAD and could report results in 2026. Key trials include the AHEAD 3-45 trial of lecanemab (Leqembi/Eisai-Biogen), and the TRAILBLAZER-ALZ 3 trial of donanemab, (Kisunla/Eli Lilly).