Cerebrospinal Fluid Biomarkers in Familial Forms of Alzheimer's Disease and Frontotemporal Dementia

Abstract

As dementia is a fast-growing health care problem, it is becoming an increasingly urgent need to provide an early diagnosis in order to offer patients the best medical treatment and care. Validated biomarkers which reflect the pathology and disease progression are essential for diagnosis and are important when developing new therapies. Today, the core protein biomarkers amyloid-β₄₂, total tau and phosphorylated tau in the cerebrospinal fluid (CSF) are used to diagnose Alzheimer's disease (AD), because these biomarkers have shown to reflect the underlying amyloid and tau pathology. However, the biomarkers have proved insufficient predictors of dementias with a different pathology, e.g. frontotemporal dementia (FTD); furthermore, the biomarkers are not useful for early AD diagnosis. Familial dementias with a known disease-causing mutation can be extremely valuable to study; yet the biomarker profiles in patients with familial dementias are not clear. This review summarizes CSF biomarker findings from studies on symptomatic and presymptomatic individuals carrying a mutation in one of the genes known to cause early-onset familial AD or FTD. In conclusion, the biomarker profile of inherited AD is quite similar between carriers of different mutations as well as similar to the profile found in sporadic AD, whereas familial FTD does not seem to have a clear biomarker profile. Hence, new biomarkers are needed for FTD.

Phenotypic Variability in Autosomal Dominant Familial Alzheimer Disease due to the S170F Mutation of Presenilin-1

“…CSF biomarkers (available in 4 patients) included reduced Aβ 42 and increased t-tau and p-tau protein, reminiscent of sporadic AD [83]. This is in line with recent investigations of larger populations suggesting that changes of CSF biomarkers are comparable in familial and sporadic AD [13,34,84].…”

Cerebrospinal Fluid BACE1 Activity and sAβPPβ as Biomarker Candidates of Alzheimer’s Disease

“…Τhe clinical usefulness of the established ΑD biomarkers, including cerebrospinal fluid (CSF) amyloid-β 1–42 (Aβ 42 ), total tau (tTau), phosphorylated tau 181 (pTau) [7, 8] and 18 F-fluorodeoxyglucose positron emission tomography (FDG PET) [9, 10], decreases when it comes to the identification of early or atypical AD, especially in unselected populations which are not enriched with relatively pure AD cases [11, 12]. Moreover, established AD biomarkers reflect events of AD pathogenesis which are downstream of the cleavage of amyloid-β pre cursor protein (AβPP) by the β-site AβPP cleaving enzyme 1 (BACE1), the initial phase of the amyloid cascade [11].…”

Cerebrospinal Fluid TAR DNA-Binding Protein 43 Combined with Tau Proteins as a Candidate Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Spectrum Disorders

“…Such a profile does not currently exist to predict TDP-43 pathology, unless there is a known associated gene mutation. Thus, a biomarker or a combination thereof is highly required [16]. Attempts to quantify TDP-43 in biological fluids of ALS and FTD patients have been infrequent and the results are contradictory [17,18,19,20], probably due to different methodologies used, sample source and collection, and set of patients versus controls.…”