Comparison of clinical characteristics between familial and non-familial early onset Alzheimer’s disease

Abstract

Although familial Alzheimer’s disease (FAD) is an early onset AD (EAD), most patients with EAD do not have a familial disorder. Recent guidelines recommend testing for genes causing FAD only in those EAD patients with two first-degree relatives. However, some patients with FAD may lack a known family history or other indications for suspecting FAD but might nonetheless be carriers of FAD mutations. The study was aimed to identify clinical features that distinguish FAD from non-familial EAD (NF-EAD). A retrospective review of a university-based cohort of 32 FAD patients with PSEN1-related AD and 81 with NF-EAD was conducted. The PSEN1 patients, compared to the NF-EAD patients, had an earlier age of disease onset (41.8 ± 5.2 vs. 55.9 ± 4.8 years) and, at initial assessment, a longer disease duration (5.1 ± 3.4 vs. 3.3 ± 2.6 years) and lower MMSE scores (10.74 ± 8.0 vs. 20.95 ± 5.8). Patients with NF-EAD were more likely to present with non-memory deficits, particularly visuospatial symptoms, than were FAD patients. When age, disease duration, and MMSE scores were controlled in a logistical regression model, FAD patients were more likely to have significant headaches, myoclonus, gait abnormality, and pseudobulbar affect than those with NF-EAD. In addition to a much younger age of onset, FAD patients with PSEN1 mutations differed from those with NF-EAD by a history of headaches and pseudobulbar affect, as well as myoclonus and gait abnormality on examination. These may represent differences in pathophysiology between FAD and NF-EAD and in some contexts such findings should lead to genetic counseling and appropriate recommendations for genetic testing for FAD.

P2‐203: Phenotypic Similarities between Late‐Onset Autosomal Dominant and Sporadic Alzheimer Disease: A Single‐Family Case‐Control Study

“…Hallucinations and delusions were reported more frequently in PSEN1 A79V MCs from this family, as has been noted previously in individuals with ADAD. 44,45 These findings demonstrate that the clinical phenotypes of late-onset ADAD and LOAD can overlap, and suggest that previously reported clinical (e.g., seizures, early myoclonus, spastic paraparesis, dysarthria, and rapid decline [9][10][11][12][13][14][15][16][17][18] ) and neuropathological differences (e.g., altered cerebral Aβ 42 and neurofibrillary tangle deposition, increased prevalence of cerebral amyloid angiopathy, and formation of "cotton wool" plaques 6,12,16,[19][20][21][22][23][24][25][26][27] ) may reflect age-or mutation-dependent effects.…”

“…7,8 Also, ADAD may be characterized by clinical features that are unusual in LOAD, including pyramidal signs, hypo/hyperkinetic movement disorders, ataxia, and early myoclonus and seizures. [9][10][11][12][13][14][15][16][17][18] Additional differences in the pattern of cerebral Aβ 42 deposition are reported in some ADAD cases, including 6,16,19,20 higher Aβ 42 burden and greater densities of neurofibrillary tangles; [21][22][23] increased Aβ 42 deposition within the cerebellum [24][25][26] and basal ganglia; 19,20 ; and higher prevalence of cerebral amyloid angiopathy and large diffuse so-called "cotton wool" plaques. 12,22,24,27 Such clinical and pathological differences may challenge whether findings from studies of early-onset ADAD, including current trials of anti-amyloid therapies, 28 can be extrapolated to the understanding of the far more common LOAD.…”

Co-morbid beta-amyloid toxicity and stroke produce impairments in an ambiguous context task in rats without any impairment in spatial working memory

“…The most frequent and widely studied neuropathologies associated with AD are decreased acetylcholine (ACh) producing neurons (Bowen, Benton, Spillane, Smith, & Allen, 1982;Perry et al, 1978;Whitehouse, Price, Clark, Coyle, & DeLong, 1981), changes in ACh producing cells' form and volume (Mesulam, Shaw, Mash, & Weintraub, 2004;Sassin et al, 2000), decreased cholinergic tone (Davies & Maloney, 1976) and increased presence of senile plaques in post-mortem samples (Joshi, Ringman, Lee, Juarez, & Mendez, 2012). The characteristic senile plaque found in AD is composed of the accumulation of beta-amyloid typically in the presence of hyperphosphorylated tau (Braak & Braak, 1991.…”

Progress in Alzheimer’s disease research in the last year

“…Joshi et al [15] compared clinical characteristics between FAD and non-familial early onset AD (NF-EAD), aiming to identify clinical features that suggest a genetic origin of the disease and that thus suggest to go on with the genetic counseling. Patients carrying a PSEN1 mutation had an earlier age at disease onset as compared with noncarriers (41.8 versus 55.9 years), and, at initial assessment, longer disease duration and lower MMSE scores.…”