Mapping the genetic landscape of early-onset Alzheimer's disease in a cohort of 36 families.

BACKGROUND: Many families with clinical early-onset Alzheimer's disease (EOAD) remain genetically unexplained. A combination of genetic factors is not standardly investigated. In addition to monogenic causes, we evaluated the possible polygenic architecture in a large series of families, to assess if genetic testing of familial EOAD could be expanded. METHODS: Thirty-six pedigrees (77 patients) were ascertained from a larger cohort of patients, with relationships determined by genetic data (exome sequencing data and/or SNP arrays). All families included at least one AD patient with symptom onset <70 years. We evaluated segregating rare variants in known dementia-related genes, and other genes or variants if shared by multiple families. APOE was genotyped and duplications in APP were assessed by targeted test or using SNP array data. We computed polygenic risk scores (PRS) compared with a reference population-based dataset, by imputing SNP arrays or exome sequencing data. RESULTS: In eight families, we identified a pathogenic variant, including the genes APP, PSEN1, SORL1, and an unexpected GRN frameshift variant. APOE-ε4 homozygosity was present in eighteen families, showing full segregation with disease in seven families. Eight families harbored a variant of uncertain significance (VUS), of which six included APOE-ε4 homozygous carriers. PRS was not higher in the families combined compared with the population mean (beta 0.05, P = 0.21), with a maximum increase of 0.61 (OR = 1.84) in the GRN family. Subgroup analyses indicated lower PRS in six APP/PSEN1 families compared with the rest (beta -0.22 vs. 0.10; P = 0.009) and lower APOE burden in all eight families with monogenic cause (beta 0.29 vs. 1.15, P = 0.010). Nine families remained without a genetic cause or risk factor identified. CONCLUSION: Besides monogenic causes, we suspect a polygenic disease architecture in multiple families based on APOE and rare VUS. The risk conveyed by PRS is modest across the studied families. Families without any identified risk factor render suitable candidates for further in-depth genetic evaluation.

Cerebrovascular disease in suspected non-Alzheimer's pathophysiology and cognitive decline over time.

BACKGROUND: The underlying cause of cognitive decline in individuals who are positive for biomarkers of neurodegeneration (N) but negative for biomarkers of amyloid-beta (A), designated as Suspected non-Alzheimer's pathophysiology (SNAP), remains unclear. We evaluate whether cerebrovascular disease (CeVD) is more prevalent in those with SNAP compared to A-N- and A+N+ individuals and whether CeVD is associated with cognitive decline over time in SNAP patients. METHODS: A total of 216 individuals from a prospective memory clinic cohort (mean [SD] age, 72.7 [7.3] years, 100 women [56.5%]) were included and were diagnosed as no cognitive impairment (NCI), cognitive impairment no dementia (CIND), Alzheimer's dementia (AD) or vascular dementia (VaD). All individuals underwent clinical evaluation and neuropsychological assessment annually for up to 5 years. Carbon 11-labeled Pittsburgh Compound B ([11 C]-PiB) or [18 F]-flutafuranol-positron emission spectrometry imaging was performed to ascertain amyloid-beta status. Magnetic resonance imaging was performed to assess neurodegeneration as measured by medial temporal atrophy ≥2, as well as significant CeVD (sCeVD) burden, defined by cortical infarct count ≥1, Fazekas score ≥2, lacune count ≥2 or cerebral microbleed count ≥2. RESULTS: Of the 216 individuals, 50 (23.1%) A-N+ were (SNAP), 93 (43.1%) A-N-, 36 (16.7%) A+N- and 37 (17.1%) A+N+. A+N+ individuals were significantly older, while A+N+ and SNAP individuals were more likely to have dementia. The SNAP group had a higher prevalence of sCeVD (90.0%) compared to A-N-. Moreover, SNAP individuals with sCeVD had significantly steeper decline in global cognition compared to A-N- over 5 years (p = 0.042). CONCLUSIONS: These findings suggest that CeVD is a contributing factor to cognitive decline in SNAP. Therefore, SNAP individuals should be carefully assessed and treated for CeVD.

The clinical promise of biomarkers of synapse damage or loss in Alzheimer's disease.

BACKGROUND: Synapse damage and loss are fundamental to the pathophysiology of Alzheimer's disease (AD) and lead to reduced cognitive function. The goal of this review is to address the challenges of forging new clinical development approaches for AD therapeutics that can demonstrate reduction of synapse damage or loss. The key points of this review include the following: Synapse loss is a downstream effect of amyloidosis, tauopathy, inflammation, and other mechanisms occurring in AD.Synapse loss correlates most strongly with cognitive decline in AD because synaptic function underlies cognitive performance.Compounds that halt or reduce synapse damage or loss have a strong rationale as treatments of AD.Biomarkers that measure synapse degeneration or loss in patients will facilitate clinical development of such drugs.The ability of methods to sensitively measure synapse density in the brain of a living patient through synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, concentrations of synaptic proteins (e.g., neurogranin or synaptotagmin) in the cerebrospinal fluid (CSF), or functional imaging techniques such as quantitative electroencephalography (qEEG) provides a compelling case to use these types of measurements as biomarkers that quantify synapse damage or loss in clinical trials in AD. CONCLUSION: A number of emerging biomarkers are able to measure synapse injury and loss in the brain and may correlate with cognitive function in AD. These biomarkers hold promise both for use in diagnostics and in the measurement of therapeutic successes.

The metabolic syndrome in a memory clinic population: relation with clinical profile and prognosis.

BACKGROUND: The metabolic syndrome (MetS) refers to a cluster of cardiovascular risk factors that is associated with an increased risk of cognitive impairment and dementia. It is unclear however, if the presence of the MetS is associated with a particular clinical profile or a different prognosis in patients with cognitive complaints or early dementia. OBJECTIVES: To compare 1) the clinical profile and 2) the prognosis of patients attending a memory clinic according to the presence or absence of MetS. DESIGN: Longitudinal cohort. SETTING: Memory clinic. PARTICIPANTS: We included and followed 86 consecutive patients (average age of 66.7 (SD 9.7)) from the Amsterdam Dementia Cohort with an MMSE>22. MEASUREMENTS: Clinical profile (neuropsychological examination, brain MRI, cerebrospinal fluid (CSF) biomarkers, clinical diagnosis) on an initial standardized diagnostic assessment was compared according to MetS status. Progression to dementia was assessed in initially nondemented patients (subjective complaints n=40, mild cognitive impairment n=24, follow-up available in 59). RESULTS: 35 (41%) patients met the MetS criteria. Demographics were similar between patients with or without the MetS. At baseline, diagnosis, cognitive performance, severity of degenerative or vascular abnormalities on MRI, and CSF amyloid and tau levels did not differ between the groups (all p>0.05). Among nondemented patients, however, MetS was associated with worse performance on executive function, attention & speed and visuoconstructive ability (z-scores, p<0.05). During a mean follow-up of 3.4years a similar proportion of patients with (4; 17%) and without (6; 17%) the MetS progressed to dementia (p=0.45). CONCLUSION: Among nondemented patients presenting at a memory clinic MetS was associated with slightly worse cognitive performance (worse on tasks assessing executive functions, visuo-constructive ability, attention & speed), but conversion rate to dementia was not increased.

Utility of imaging for nutritional intervention studies in Alzheimer's disease.

Alzheimer's disease (AD) is a multi-factorial neurodegenerative disorder and the leading cause of dementia, wherein synapse loss is the strongest structural correlate with cognitive impairment. Basic research has shown that dietary supply of precursors and co-factors for synthesis of neuronal membranes enhances the formation of synapses. Daily intake of a medical food containing a mix of these nutrients for 12 weeks in humans improved memory, measured as immediate and delayed verbal recall by the Wechsler Memory Scale-revised, in patients with very mild AD (MMSE 24-26). An improvement of immediate verbal recall was noted following 24 weeks of intervention in an exploratory extension of the study. These data suggest that the intervention may improve synaptic formation and function in early AD. Here we review emerging technologies that help identify changes in pathological hallmarks in AD, including synaptic function and loss of connectivity in the early stages of AD, before cognitive and behavioural symptoms are observable. These techniques include the detection of specific biomarkers in the cerebrospinal fluid, as well as imaging procedures such as fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET), amyloid PET, structural/functional magnetic resonance imaging, diffusion tensor imaging, magnetoencephalography (MEG) and electroencephalography (EEG). Such techniques can provide new insights into the functional and structural changes in the brain over time, and may therefore help to develop more effective AD therapies. In particular, nutritional intervention studies that target synapse formation and function may benefit from these techniques, especially FDG-PET and EEG/MEG employed in the preclinical or early stages of the disease.

Glycemia and levels of cerebrospinal fluid amyloid and tau in patients attending a memory clinic.

OBJECTIVES: To determine the association between markers of glycemia and cerebrospinal fluid (CSF) amyloid beta 1-42 (Abeta42) and tau levels in patients attending a memory clinic. DESIGN: Cross-sectional study. SETTING: Memory clinic. PARTICIPANTS: Two hundred forty-five consecutive patients attending a memory clinic. Clinical diagnoses were subjective cognitive complaints (n=91), mild cognitive impairment (n=62), Alzheimer's disease (n=58), and other dementia (n=34). Twenty-one patients had diabetes mellitus. MEASUREMENTS: Glycosylated hemoglobin (HbA1c); fasting blood glucose levels; and CSF levels of Abeta42, total tau, and p-tau 181. RESULTS: In regression analyses across the whole study sample adjusted for age, sex, and diagnostic group, there was no relationship between HbA1c or fasting glucose and CSF tau, p-tau 182, or Abeta42 levels. Stratification for diabetes mellitus did not change the results. CONCLUSION: These observations do not support the hypothesis that the association between dysglycemia and impaired cognitive functioning is mediated through aberrant amyloid or tau metabolism.