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Clinically Important Benefits and Harms of Monoclonal Antibodies Targeting Amyloid for the Treatment of Alzheimer Disease: A Systematic Review and Meta-Analysis

Author/s: 
Mark H Ebell, Henry C Barry, Kanishka Baduni, Gabrielle Grasso

Purpose: We conducted a meta-analysis to evaluate clinically meaningful benefits and harms of monoclonal antibodies targeting amyloid in patients with Alzheimer dementia.

Methods: We searched PubMed, Cochrane CENTRAL, and 5 trial registries, as well as the reference lists of identified studies. We included randomized controlled trials comparing a monoclonal antibody with placebo at a dose consistent with that used in phase 3 trials or for Food and Drug Administration approval. Studies had to report at least 1 clinically relevant benefit or harm. Data were extracted independently by at least 2 researchers for random effects meta-analysis. Changes in cognitive and functional scales were compared between groups, and each difference was assessed to determine if it met the minimal clinically important difference (MCID).

Results: We identified 19 publications with 23,202 total participants that evaluated 8 anti-amyloid antibodies. There were small improvements over placebo in the Alzheimer's Disease Assessment Scale (ADAS)-Cog-11 to -14 score (standardized mean difference = -0.07; 95% CI, -0.10 to -0.04), Mini Mental State Examination score (0.32 points; 95% CI, 0.13 to 0.50), and Clinical Dementia Rating-Sum of Boxes scale score (mean difference =-0.18 points; 95% CI, -0.34 to -0.03), and the combined functional scores (standardized mean difference = 0.09; 95% CI, 0.05 to 0.13). None of the changes, including those for lecanemab, aducanumab, and donanemab, exceeded the MCID. Harms included significantly increased risks of amyloid-related imaging abnormalities (ARIA)-edema (relative risk [RR] = 10.29; number needed to harm [NNH] = 9), ARIA-hemorrhage (RR = 1.74; NNH = 13), and symptomatic ARIA-edema (RR = 24.3; NNH = 86).

Conclusions: Although monoclonal antibodies targeting amyloid provide small benefits on cognitive and functional scales in patients with Alzheimer dementia, these improvements are far below the MCID for each outcome and are accompanied by clinically meaningful harms.

Keywords: ARIA; Alzheimer dementia; Alzheimer disease; aducanumab; aged; amyloid; antibodies, monoclonal; biological therapy; cerebral edema; cerebral hemorrhage; chronic disease; dementia; donanemab; drug approval; lecanemab; meta-analysis; risks and benefits; systematic review.

Keywords 
Alzheimer dementia Alzheimer Disease biological therapy cerebral edema cerebral hemorrhage dementia

Frontotemporal dementia

Author/s: 
Raul Medina-Rioja, Gina Gonzalez-Calderon, Mario Masellis

Frontotemporal dementia should be considered in adults aged 50–75 years presenting with behavioural or language changes. After Alzheimer disease, it is the second most common cause of dementia among adults younger than 65 years.1 Frontal and temporal lobe degeneration results in behavioural or language impairment.

Keywords 
Frontotemporal Dementia neurology dementia Alzheimer Disease

APOE ɛ4 Allele Testing and Risk of Alzheimer Disease

Author/s: 
Choudhury, Parichita, Ramanan, Vijay K., Boeve, Bradley F.

A 64-year-old man presented with concern about an abnormal genetic test result for apolipoprotein E (APOE) obtained through his primary care physician. He reported forgetfulness and word-finding difficulties for 3 years but performed all activities of daily living independently and was generally healthy. His father and maternal great aunt developed dementia in their 70s. Physical (including neurologic) examination, basic laboratory studies, and brain magnetic resonance imaging results were normal. The Short Test of Mental Status (STMS) score was 33 (maximal attainable score of 38 indicates best performance). Neuropsychological assessment showed average to above-average performance in all cognitive domains, accounting for age and education. Results of his genetic testing for APOE were reported as follows: “This individual possesses an apolipoprotein E genotype (3 and 4) that indicates, with high specificity, that Alzheimer’s disease is the cause of or a contributor to the observed dementia.”

Keywords 
Alzheimer Disease aged elderly Elderly care elderly patients

APOE ɛ4 Allele Testing and Risk of Alzheimer Disease

Author/s: 
Choudhury, Parichita, Boeve, Bradley F., Ramanan, Vijay K

A 64-year-old man presented with concern about an abnormal genetic test result for apolipoprotein E (APOE) obtained through his primary care physician. He reported forgetfulness and word-finding difficulties for 3 years but performed all activities of daily living independently and was generally healthy. His father and maternal great aunt developed dementia in their 70s. Physical (including neurologic) examination, basic laboratory studies, and brain magnetic resonance imaging results were normal. The Short Test of Mental Status (STMS) score was 33 (maximal attainable score of 38 indicates best performance). Neuropsychological assessment showed average to above-average performance in all cognitive domains, accounting for age and education. Results of his genetic testing for APOE were reported as follows: “This individual possesses an apolipoprotein E genotype (3 and 4) that indicates, with high specificity, that Alzheimer’s disease is the cause of or a contributor to the observed dementia.

Keywords 
dementia Alzheimer Disease Genetic testing

The Potential Emergence of Disease-Modifying Treatments for Alzheimer Disease: The Role of Primary Care in Managing the Patient Journey

Author/s: 
Lam, J., Hlávka, J., Mattke, S.

Despite recent setbacks, disease-modifying treatments (DMTs) for Alzheimer disease (AD) might become available within a few years. These DMTs are likely to be used in the early stages of AD to avoid the progression to manifest dementia, which implies that a large reservoir of prevalent cases would need to be evaluated when DMTs first become available. Primary care providers (PCPs) would play a vital role in managing the patient flow to specialty care. We review the literature on diagnostic tests that could be used by PCPs and estimate the impact of different testing approaches on demand for specialty care.While many tests have been evaluated, only the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) perform acceptably for detection of early-stage cognitive decline with sensitivities and specificities of 55% to 82% and 72% to 84%, respectively, for the MMSE; and 77% to 96% and 73% to 95%, respectively, for the MoCA. However, neither test is sufficiently specific for the AD pathology and would result in 4 to 5 false positives for each true positive. Blood-based tests for AD biomarkers may soon become available for clinical use. A plasma amyloid-β (Aβ) test has been shown to have a sensitivity of up to 97% and specificity of up to 81%. Adding this test to the MMSE or MoCA could reduce false positives by approximately 80%.These findings suggest a combination of brief cognitive tests and blood-based biomarker tests will allow PCPs to identify patients with potential early stage AD efficiently and triage them for further evaluation.

Keywords 
Alzheimer Disease
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