Louisville Medicine Volume 69, Issue 8 - Page 15

Alois Alzheimer - Image from the History of Medicine ( NLM )
million by 2060 . 2 The insurmountable economic burden that AD will bestow upon society calls for urgent measures directed at improving the diagnosis and treatment . Alzheimer ’ s disease is still a clinical diagnosis , based on progressive deterioration of memory , cognition and other higher functions . At present , if there is concern about Alzheimer ’ s disease , the initial steps are neuropsychological assessment and MRI of the brain . The imaging findings may be non-specific in that cortical atrophy can be seen in other forms of dementia as well ; but it is an essential test as it will detect treatable causes of dementia like normal pressure hydrocephalus . Often , no more tests are done currently other than blood work to rule out treatable causes like hypothyroidism . However , more conclusive diagnosis of AD can be made by PET scan using amyloid radiopharmaceutical , which tags the plaques , or Tau PET tracer that tags the neurofibrillary tangles .
FEATURE
Let us look at the new developments in AD . It is still a challenge to get the health insurance companies to pay for the amyloid / Tau PET scans . This has led to development of biomarkers that can predict a positive amyloid PET scan . Initial studies concentrated on CSF biomarkers such as levels of β amyloid and tau proteins . The “ CSF signatures ” of AD include a significant decrease in Aβ42 and Aβ42 / Aβ40 ratio as well as an increase in total tau and P-tau 181 . Clinical trials of drugs for AD use amyloid PET scan and CSF biomarkers as objective criteria for showing effectiveness . It became increasingly clear that more simple tests are needed to monitor progress rather than serial lumbar punctures and PET scans . This need has prompted much research into biomarkers in blood , further facilitated by innovative technology like immunoprecipitation mass spectrometry . Using such techniques , Aβ42 and Aβ42 / Aβ40 ratio in the blood was found to be a sensitive predictor of amyloid accumulation in the brain . A combination of amyloid ratio , ApoE status and patient ’ s age agreed with results of amyloid PET scan in 94 % of cases ; this test has become commercially available in 2019 , although it is still not covered by medical insurance carriers .
2021 saw the first steps towards disease-modifying therapy in AD . The recent accelerated approval of aducanumab ( a human recombinant anti-A IgG1monoclonal antibody ) was perhaps the most exciting development . It binds to and induces removal of aggregated forms of Aβ . Many considered it a hasty decision by the FDA as the evidence for clinical benefit was not particularly strong . This led to modification of its original decision , such that the drug may be given only to patients in the early stage of AD . The annual cost is $ 56,000 , and it is given by monthly infusion . Two more drugs , lecanemab and donanemab are in advanced stages of clinical trials , waiting for approval . One could expect many more soon .
What will the future hold for AD ? If the blood tests for biomarkers are as sensitive as CSF biomarkers and PET scan , they will revolutionize management of AD . It should be possible to predict the risk for developing AD , decades before the onset of dementia . This will open the door for disease modifying measures that may eventually prevent AD . We are on the verge of a new era of biomarker-supported diagnosis and molecular-specific therapies in AD .
Let me close with an apt quote from Dr . William James Mayo : “ The glory of medicine is that it is constantly moving forward , that there is always more to learn . The ills of today do not cloud the horizon of tomorrow , but act as a spur to greater effort .”
Abbreviations : AD : Alzheimer ’ s disease ; Aβ : amyloid beta ; APOE : apolipoprotein E
References :
1
Guam ’ s “ Skeleton Key ” Enigma . Penn Medicine Magazine . Archived issues 2017
2
Brookmeyer et al . Forecasting the prevalence of preclinical and clinical Alzheimer ’ s disease in the United States . Alzheimer ’ s Dement . 2018 ; 14 ( 2 ): 121- 129
3
Schindler SE et al . High-precision plasma β-amyloid 42 / 40 predicts current and future brain amyloidosis . Neurology . 2019 ; 93 ( 17 )
4
Kirmess KM et al . The PrecivityAD TM test : Accurate and reliable LC-MS / MS assays for quantifying plasma amyloid beta 40 and 42 and apolipoprotein E prototype for the assessment of brain amyloidosis . Clin Chem . 2021 ; 519 : 267- 275
Dr . Iyer practices at the Neurodiagnostic Center of Louisville and is a retired professor of neurology at the University of Louisville School of Medicine .
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