Premium content
Lecanemab slowed decline by 0.45 CDR-SB points (27%) in CLARITY AD; donanemab by 22–36% in TRAILBLAZER-ALZ 2. Does the small class-wide effect in Cochrane CD016297 cancel those results — and what do two widely shared podcast claims about harm and reversal get wrong?
Lecanemab binds soluble protofibrils and is dosed continuously; donanemab binds pyroglutamate plaque amyloid and can be stopped after clearance. How that difference shapes dosing, MRI schedules, and ARIA counseling for APOE ε4 carriers.
In CLARITY AD, lecanemab slowed decline on CDR-Sum of Boxes by 0.45 points over 18 months (95% CI −0.67 to −0.23; P<0.001), with amyloid-related imaging abnormalities involving edema or effusion in 12.6% of 1,795 participants. Those events are not evenly distributed across genotypes, and ε4 homozygotes carry the highest risk — which is why APOE genotyping now forms part of pre-treatment risk assessment. This guide covers registry search, the four criteria that disqualify most applicants, and what to ask a coordinator before consenting.
A typical primary care visit runs fifteen minutes, and most clinicians encounter APOE results rarely and without clinical context. The two predictable failure modes are brisk reassurance that changes nothing, or an unplanned testing cascade. These four frameworks — consumer genetic result, biomarker request, cardiometabolic management, and referral for a symptomatic relative — are built on one principle: replace an unanswerable question with a specific one your physician can act on.
Two randomized trials have now tested whether APOE ε4 carriers benefit more from multidomain lifestyle intervention than non-carriers. FINGER’s prespecified subgroup analysis returned an interaction estimate of 0.023 with a confidence interval crossing zero; US POINTER, with 2,111 participants, returned P=.95 for interaction. The carrier-advantage claim used to justify ε4-specific protocols is not supported. This review ranks what does have evidence — and gives equal space to the trials that failed.
In 4,807 older adults, statin initiation was associated with a 40% lower risk of incident Alzheimer disease among APOE ε4 carriers (HR 0.60, 95% CI 0.49–0.74) and no measurable benefit in non-carriers (HR 0.96; interaction p=0.015). It is one of the few genotype-stratified laboratory findings that survives scrutiny — and it does not produce an APOE-specific lipid target. This assessment separates the tests with evidence behind them from those being marketed to carriers.
LDL cholesterol rises linearly across APOE genotype, but coronary risk does not follow it. Bennet et al. (JAMA 2007; n=86,067) found a 44 mg/dL spread between the genotype extremes — and a coronary odds ratio in ε4 carriers of just 1.06 (95% CI 0.99–1.13). Three separate risk quantities are routinely quoted interchangeably in clinic, and only one of them belongs in a disclosure conversation.
A clinical review of whether APOE ε4-associated risk can be normalized through modifiable intervention — examining multidomain prevention trial evidence, the distinction between relative and absolute risk reduction, and the boundary between what current data support and what they do not.
A minority of APOE ε4 homozygotes reach advanced age without dementia. This review examines the distinction between resistance to amyloid pathology and resilience despite it, the protective variants and mechanisms implicated to date, and what these exceptional cases do — and do not — establish about modifiable risk in ε4/ε4 carriers.
An Alzheimer’s blood biomarker and an APOE genotype test answer fundamentally different clinical questions: one indicates whether disease pathology is present now, the other estimates lifetime susceptibility. This article explains what each test can establish, what neither can, and how the two are interpreted together.