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Data from: INTREPAD: a randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease
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Meyer, Pierre-Francois; Tremblay-Mercier, Jennifer; Leoutsakos, Jeannie; Madjar, Cecile; Lafaille-Magnan, Marie-Elyse; Savard, Melissa; Rosa-Neto, Pedro; Poirier, Judes; Etienne, Pierre; Breitner, John — 2019-05-03 Objective: Evaluate the safety and efficacy of low-dose naproxen for prevention of progression in pre-symptomatic AD among cognitively intact persons at-risk. Methods: INTREPAD, a two-year double-masked pharmaco-prevention trial, enrolled 195 AD family history-positive elderly (mean age 63 years) screened carefully to exclude cognitive disorder. These were randomized 1:1 to naproxen sodium 220mg twice-daily or placebo. Multimodal imaging, neurosensory, cognitive and (in ~50%) CSF biomarker evaluations were performed at Baseline, 3, 12, and 24 months. A modified intent-to-treat analysis considered 160 participants who remained on-treatment through their first follow-up examination. The primary outcome was rate of change in a multimodal composite pre-symptomatic Alzheimer Progression Score (APS). Results: Safety: Naproxen-treated individuals showed a clear excess of adverse events. Efficacy: Among treatment groups combined, the APS increased by 0.101 points/year (S.E = 0.014; P < 10-5), but rate of change showed little difference by treatment assignment (0.017 points/year). The treatment-related slope ratio of 1.10 (95% Confidence Interval 0.588–2.04) suggested that naproxen does not reduce the rate of APS progression by more than 41%. Secondary analyses revealed no notable treatment effects on individual CSF, cognitive, or neurosensory biomarker indicators of progressive pre-symptomatic AD. Conclusions: In cognitively intact individuals at-risk, sustained treatment with naproxen sodium 220 mg twice-daily increases frequency of adverse health effects but does not reduce apparent progression of pre-symptomatic AD. Classification of Evidence: This study provides Class I evidence that, for people who are cognitively intact, low-dose naproxen does not significantly reduce progression of a composite indicator of pre-symptomatic AD.
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Education is associated with Aβ burden in preclinical familial and sporadic Alzheimer’s disease
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Gonneaud, Julie; Bedetti, Christophe; Pichet Binette, Alexa; Benzinger, Tammie; Morris, John; Bateman, Randall; Poirier, Judes; Breitner, John; Villeneuve, Sylvia — 2021-03-31 <p class="1Paragraph" style="border:none;"><span><b>Objective.</b> To determine whether years of education and the ε4 risk allele at <i>APOE</i> influence β-amyloid pathology similarly in asymptomatic individuals with a family history of sporadic Alzheimer’s disease (AD) and pre-symptomatic autosomal dominant AD mutation carriers. </span></p> <p class="1Paragraph" style="border:none;"><span><b>Methods.</b> We analyzed cross-sectional data from 106 asymptomatic individuals with a parental history of sporadic AD (PREVENT-AD cohort; age=67.28±4.72 years) and 117 pre-symptomatic autosomal dominant AD mutation carriers (DIAN cohort; age=34.00±9.43 years). All participants underwent structural MRI and β-amyloid PET imaging. In each cohort we investigated the influence of years of education, <i>APOE</i>-ε4 status and their interaction on β-amyloid PET. </span></p> <p><span><b>Results. </b>Asymptomatic individuals with a parental history of sporadic AD showed increased β-amyloid burden associated with <i>APOE</i>-ε4 carriage and lower level of education, but no interaction between these. Pre-symptomatic mutation carriers of autosomal dominant AD showed no relation between <i>APOE-</i>ε4 and β-amyloid burden, but increasing level of education was associated with reduced β-amyloid burden. The association between educational attainment and β-amyloid burden was similar in the two cohorts. </span></p> <p><b>Conclusions. </b>While the <i>APOE</i>-ε4 allele confers increased tendency toward β-amyloid accumulation in sporadic AD only, protective environmental factors, like increased education, may promote brain resistance against β-amyloid pathology   in both sporadic and autosomal dominant AD.</p>

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(Author: Breitner, John)

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