Presenile Alzheimer's Disease Research Articles

Early-stage differentiation between presenile Alzheimer's disease and frontotemporal dementia using arterial spin labeling MRI.

ObjectiveTo investigate arterial spin labeling (ASL)-MRI for the early diagnosis of and differentiation between the two most common types of presenile dementia: Alzheimer’s disease (AD) and frontotemporal dementia (FTD), and for distinguishing age-related from pathological perfusion changes.MethodsThirteen AD and 19 FTD patients, and 25 age-matched older and 22 younger controls underwent 3D pseudo-continuous ASL-MRI at 3 T. Gray matter (GM) volume and cerebral blood flow (CBF), corrected for partial volume effects, were quantified in the entire supratentorial cortex and in 10 GM regions. Sensitivity, specificity and diagnostic performance were evaluated in regions showing significant CBF differences between patient groups or between patients and older controls.ResultsAD compared with FTD patients had hypoperfusion in the posterior cingulate cortex, differentiating these with a diagnostic performance of 74 %. Compared to older controls, FTD patients showed hypoperfusion in the anterior cingulate cortex, whereas AD patients showed a more widespread regional hypoperfusion as well as atrophy. Regional atrophy was not different between AD and FTD. Diagnostic performance of ASL to differentiate AD or FTD from controls was good (78-85 %). Older controls showed global hypoperfusion compared to young controls.ConclusionASL-MRI contributes to early diagnosis of and differentiation between presenile AD and FTD.Key Points• ASL-MRI facilitates differentiation of early Alzheimer’s disease and frontotemporal dementia.• Posterior cingulate perfusion is lower in Alzheimer’s disease than frontotemporal dementia.• Compared to controls, Alzheimer’s disease patients show hypoperfusion in multiple regions.• Compared to controls, frontotemporal dementia patients show focal anterior cingulate hypoperfusion.• Global decreased perfusion in older adults differs from hypoperfusion in dementia.

A Fatal Fall Associated With Undiagnosed Parenchymatous Neurosyphilis

A fall from a great height is often associated with altered mental status. Aside from the usual contributing factors, for example, alcohol consumption or mental illness, natural disease leading to a fatal fall is seldom identified by autopsy. The case described in this report is that of a 57-year-old man who had been clinically diagnosed with presenile Alzheimer disease and fell head first into a river from the bridge. These events were captured by a surveillance camera on the bridge; an acquaintance reported that he had previous suicidal ideation. At autopsy, the cervical spinal cord was determined to have been severely injured, and the sixth cervical vertebra was observed to have been fractured. Histological examination showed chronic meningoencephalitis including neuronal loss, perivascular cuffing, and the proliferation of microglia and astrocytes in the cerebral cortex. Serologic evaluation consisting of the nontreponemal antigen test (rapid plasma reagin [RPR]) and treponemal antibody test (Treponema pallidum latex agglutination) was positive in both cases (RPR: 18.2 RPR units, T. pallidum latex agglutination: 7718 U/mL). These findings suggested that the patient had been affected by a syphilis infection and that his suicidal behavior was associated with parenchymatous neurosyphilis.

Constructional Apraxia as a Distinctive Cognitive and Structural Brain Feature of Pre-Senile Alzheimer's Disease

Constructional apraxia (CA) is often, but not always, observed in patients with Alzheimer's disease (AD). CA is usually explained by impairment of either basic perceptual and motor abilities, or executive functions. This study aims to evaluate the structural correlates of CA in AD. Forty-eight patients with AD and 20 healthy age-matched controls underwent a thorough neuropsychological investigation and an MRI scan to collect high-resolution T1-weighted data. Patients were classified as having (ADca) or not having (ADnonca) CA based on performance on the Freehand copying of drawings task. T1-weighted volumes were process according to the voxel based morphometry protocol, to assess the presence of significant differences in local to grey matter volumes in patients compared to controls and in ADca compared to ADnonca. Post-hoc, the mean grey matter volume of clusters that resulted significantly different between groups was regressed against the neuropsychological scores in which the two patient groups performed differently. A pre-senile disease onset was significantly more frequent in patients with CA compared to ADnonca. ADca patients also showed worse performances than patients with ADnonca at some tests requiring the processing of visuo-spatial data and testing working memory. They also showed widespread reductions in grey matter volume, mainly located in areas known to be implicated in object recognition and localization, and in maintenance and re-orienting of spatial attention. These findings suggest that the occurrence of CA in AD is often associated with a peculiar clinical onset (i.e., pre-senile), neuropsychological profile, and distribution of grey matter atrophy.

Sensitivity and specificity of FTDC criteria for behavioral variant frontotemporal dementia

We aimed to assess sensitivity and specificity of the updated criteria for behavioral variant frontotemporal dementia (bvFTD) based on a large autopsy-confirmed cohort of patients with dementia. Two hundred thirty-nine consecutive pathologically confirmed dementia patients, clinically assessed in a specialist cognitive unit were identified. Patients with predominant aphasia, motor disorders, or insufficient clinical information were excluded. Frontotemporal Dementia Consensus criteria were applied to anonymized clinical data taken from patients' initial assessment by raters who were blinded to clinical and pathologic diagnosis. The final study cohort comprised 156 patients with predominantly early-onset dementia. The updated criteria for possible bvFTD had a sensitivity of 95% and specificity of 82%. Probable bvFTD criteria had a sensitivity of 85% and specificity of 95%. False positives were predominantly patients with presenile Alzheimer disease. Revised diagnostic criteria show encouragingly high sensitivity and specificity when applied to patients with early-onset dementia. They therefore provide a useful tool both for specialist researchers and general clinicians. There is a need for further prospective studies of sensitivity and specificity involving a broader spectrum of patients with dementia.

Juvenile dementia and review of pathological findings of very early presenile Alzheimer's disease

Although AD usually occurs in the elderly, it can also develop in younger patients. Studies on neuropathological findings in early onset AD are scarce. Our aims are threefold: to study (1) neuropathological findings in a case of juvenile, familial AD due to a novel mutation in PSEN1 Ser170Phe (exon 6, c.509C > T) (Rademakers en Van Broeckhoven), (2) to review a series of 43 early onset cases with various mutations (starting symptoms 19-36y mean 31y; death 28-60 y mean 40 y), (3) to study the relationship between regional distribution of Alzheimer pathology and age-at-onset in a cohort of 30 AD autopsies with a wide variability in age-at-onset. In the review of 43 early onset cases, brain weight and regional atrophy were assessed. Furthermore, microscopic measures including congophilic angiopathy, cotton wool plaques and distribution of plaques and tangles were obtained. The case with the novel mutation PSEN1 Ser170Phe was a young woman starting with learning problems in school followed by forgetfulness from age of 19 years who died at 29 deeply demented. From the series of early onset cases, the weight of 27 brains was known: mean 952 g (range 550-1300 g; man 1007 g (range 550-1300); women 883 g (range 600-1185). 28 out of 43 patients had amyloid angiopathy (including 3 with cerebellar CAA). According to description most atrophy was located frontotemporally or was described as “diffuse”. Brainstem involvement (plaques, tangles) was seen in 8 patients (18.6%), spinal cord involvement in 6 patients (13.9%). Cotton wool plaques were found in 14 patients (32.6%). In a comparison of 15 patients with a remarkable parietal tangle distribution with patients with 15 patients with prominent temporal involvement, it was shown that dementia occurred on average 10 years earlier in the patients with a marked parietal tangle distribution (p < 0.05). Juvenile or early forms dementia do not differ histologically from diffuse forms of senile dementia except that cotton wool plaques can be found in a subset. However brain weight is lower, the spinal cord can be affected as well and the parietal cortex is more prominently affected in AD cases with early onset.

The Usefulness of Biological and Neuroimaging Markers for the Diagnosis of Early-Onset Alzheimer's Disease

The recent proposed criteria for Alzheimer's Disease (AD) have strongly claimed the usefulness of biological and neuroimaging markers for early identification AD. Cerebrospinal fluid (CSF) Tau/Abeta ratio, hippocampal atrophy, posterior cingulate, and neocortical associative area hypometabolism, or amyloid burden evaluated by PiB compound, held the premises to increase diagnostic accuracy in the preclinical disease stages. Despite many efforts to identify subjects at risk of developing AD, less attention has been paid to presenile AD diagnosis. A few data are already available in early onset AD, mainly obtained in cases of monogenic disorder. In this paper, we discuss the current literature on the role of biological and neuroimaging markers in presenile AD.

Apport diagnostic des marqueurs biologiques de la maladie d’Alzheimer (MA) dans une observation de dégénérescence lobaire fronto-temporale (DLFT)

Cerebrospinal fluid biomarkers are a fundamental contribution for the diagnosis of Alzheimer disease, in particular for young people. We report a case of Alzheimer disease of a 51-years old man whose clinical presentation corresponded to frontotemporal behavioural criteria. The clinical evaluation noticed some troubles in verbal memory. Only the CSF biomarkers confirmed the diagnosis. There are different phenotypes of presenile Alzheimer disease and among them we note frontotemporal dementia. It is very important to identify them to introduce a specific treatment.

Assessment of EEG dynamical complexity in Alzheimer’s disease using multiscale entropy

Multiscale entropy (MSE) is a recently proposed entropy-based index of physiological complexity, evaluating signals at multiple temporal scales. To test this method as an aid to elucidating the pathophysiology of Alzheimer's disease (AD), we examined MSE in resting state EEG activity in comparison with traditional EEG analysis. We recorded EEG in medication-free 15 presenile AD patients and 18 age- and sex-matched healthy control (HC) subjects. MSE was calculated for continuous 60-s epochs for each group, concurrently with power analysis. The MSE results from smaller and larger scales were associated with higher and lower frequencies of relative power, respectively. Group analysis demonstrated that the AD group had less complexity at smaller scales in more frontal areas, consistent with previous findings. In contrast, higher complexity at larger scales was observed across brain areas in AD group and this higher complexity was significantly correlated with cognitive decline. MSE measures identified an abnormal complexity profile across different temporal scales and their relation to the severity of AD. These findings indicate that entropy-based analytic methods with applied at temporal scales may serve as a complementary approach for characterizing and understanding abnormal cortical dynamics in AD.

Clinical-Genetic Correlations in Familial Alzheimer's Disease Caused by Presenilin 1 Mutations

We describe the clinical phenotype of nine kindred with presenile Alzheimer's disease (AD) caused by different presenilin 1 (PS1) point mutations, and compare them with reported families with mutations in the same codons. Mutations were in exon 4 (Phe105Val), exon 5 (Pro117Arg, Glu120Gly), exon 6 (His163Arg), exon 7 (Leu226Phe), exon 8 (Val261Leu, Val272Ala, Leu282Arg), and exon 12 (Ile439Ser). Three of these amino acid changes (Phe105Val, Glu120Gly, and Ile439Ser) had not been previously reported. Distinct clinical features, including age of onset, symptoms and signs associated with the cortical-type dementia and aggressiveness of the disease, characterized the different mutations and were quite homogeneous across family members. Age of onset fell within a consistent range: some mutations caused the disease in the thirties (P117R, L226F, V272A), other in the forties (E120G, H163R, V261L, L282R), and other in the fifties (F105V, I439S). Associated features also segregated with specific mutations: early epileptic activity (E120G), spastic paraparesis (V261L), subcortical dementia and parkinsonism (V272A), early language impairment, frontal signs, and myoclonus (L226F), and late myoclonus and seizures (H163R, L282R). Neurological deterioration was particularly aggressive in PS1 mutations with earlier age of onset such as P117R, L226F, and E120G. With few exceptions, a similar clinical phenotype was found in families reported to have either the same mutation or different amino acid changes in the same codons. This series points to a strong influence of the specific genetic defect in the development of the clinical phenotype.

Quantitative EEG in patients with presenile and senile dementia of the Alzheimer type

EEG data obtained from 27 patients with presenile Alzheimer's disease (AD) and 28 patients with senile dementia of the Alzheimer type (SDAT) were compared with data from 30 age- and sex-matched controls. Both patient groups exhibited more pronounced delta and theta activity and less prominent alpha and beta activity than the controls. AD, however, was accompanied by more severe slowing than SDAT. The slowing was distributed in the left temporal and frontal regions in AD, and bilaterally in the frontal regions in SDAT. As the severity of the dementia increased, delta activity alone increased in AD, whereas, there were significantly greater increases in both delta and theta activity and decreases in alpha and beta activity in SDAT. These EEG differences appear to be related to the degree of brain damage and the speed of progression of the disease process.

Lithium may be useful in the prevention of Alzheimer’s disease in individuals at risk of presenile familial Alzheimer’s disease

Alzheimer's disease (AD) is the most common form of dementia among older people. Presenile familial AD (FAD) and sporadic Alzheimer's disease (SAD) have identical brain lesions, containing senile plaques with beta-amyloid (Abeta) peptide and neurofibrillary tangles formed by hyperphosphorylation of a microtubule-associated protein known as tau. However, FAD and SAD differ in onset and genetic transmission. Unlike SAD, presenile FAD is transmitted as a pure autosomal dominant trait. The authors suggest that lithium could be used for AD prevention, particularly in individuals at risk of presenile FAD, which has early onset. Evidence supporting this hypothesis suggests that lithium decreases Abeta peptide production and inhibits the activity of glycogen synthase kinase-3 which induces aggregation of tau protein into tangles, and tau hyperphosphorylation. Prevalence of AD is lower in patients with chronic lithium treatment, which also increases brain-derived neurotrophic factor activity, so might prevent onset in patients at risk for AD. Several considerations are suggested for prevention trials: the effect of lithium could be evaluated in young animal models that express presenile FAD mutant genes; the time, dose, duration and monitoring of lithium therapy are considered; early phenotypes could be monitored for treatment effect; and some other agents, like valproic acid, could also be candidates for prevention.

Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus

Adult proliferation and hippocampal neurogenesis are stimulated by injury. In agreement, aberrant cell-cycle-related protein expression has been reported in senile Alzheimer's disease (AD), where the hippocampus is particularly affected. Recently, increased expression of doublecortin (DCX), a neurogenesis marker, was reported in senile AD. Here, we addressed whether proliferative and neurogenic responses also occur in younger, i.e., presenile AD cases, using immunohistochemistry for Ki-67, GFAP and DCX. Increased numbers of Ki-67+ cells with a healthy, non-mature appearance were found in CA1-3. These were mainly due to glial and vasculature-associated changes, while DCX immunostaining appeared sensitive to postmortem breakdown. We found no indications for altered dentate gyrus neurogenesis. Our data obtained using validated methodology in a well-characterized, presenile cohort thus differ from previous data obtained in senile AD. They reflect clear differences in proliferative responsivity, particularly in the glia and vascular components, and suggest different underlying mechanisms in these groups.

Hyperphosphorylated tau protein in the cerebrospinal fluid of patients with Alzheimer's disease and other dementias: preliminary findings.

Alzheimer's disease (AD) is pathologically characterized by the accumulation of amyloid plaques and tau-associated neurofibrillary tangles in the cerebral tissue. The search for antemortem biomarkers is intense including analysis of cerebrospinal fluid (CSF) beta-amyloid and tau proteins concentrations seeking for an accurate and early diagnosis. Levels of hyperphosphorylated tau at threonine 181 were measured in the CSF of 34 patients with AD (19 with senile AD - SAD and eight with presenile AD - PSAD) and seven with other dementias (OD). The levels of CSF phosphotau were significantly higher in the AD patients compared to OD (AUC 0.812), with no association with severity of dementia, age of onset, duration of the disease or scores in the Mini-Mental State Examination. There were no differences of phosphotau levels between SAD and PSAD patients. These findings corroborate some previous studies and indicate that CSF phosphotau may help to differentiate AD from other dementias.

A neurologist's view of Alzheimer's disease and dementia

Senile dementia was the third most common admission diagnosis for New York psychiatric hospitals at the start of the twentieth century and the distinction between vascular and senile dementia was understood by psychiatrists even then. The term Alzheimer's disease (AD) was originally introduced to distinguish a pre-senile dementia from the common general paresis, but Alzheimer raised the possibility that pre-senile AD might not be distinguishable in clinical or histological terms from senile dementia. By the late 1970s it had become clear that the most common disorder producing dementia in elderly people was clinically and pathologically identical to pre-senile AD. AD is malignant, reducing remaining life expectancy by almost half and raising the risk of death over five years threefold (cancer raises it fourfold). Synapse loss associated with beta amyloid oligomers is a strong determinant of cognitive decline in patients with AD. Tau-containing neurofibrillary tangles usefully track disease severity. Unmodifiable risk factors include mutations in three genes which affect the production or metabolism of beta amyloid, the risk factor gene for Apolipoprotein [see symol in text]4 and female gender. The overriding risk factor is age, the prevalence of AD doubling with every five years of age until 90. Low education, head injury and low folate levels are examples of potentially modifiable risk factors. Since a delay of onset of five years would halve the number of patients with the disease, clinical trials for such putative protective factors as estrogens, folic acid, vitamin E, statins, and NSAIDs have begun. Cognitive and leisure activity may be protective against the development of AD but any protective function can only be confirmed by clinical trials.

Demencia y patrón de deterioro cognitivo: asociación con el alelo e4 de la apolipoproteína E

The APOE epsilon4 allele is a well-established risk factor for Alzheimer's disease. This disease is characterized by a typical progressive cognitive impairment pattern, different from that of other primary dementias such as dementia with Lewy bodies or frontotemporal and vascular dementias, for which there are no conclusive results on the influence of the APOE genotype. Our aim is to study how the APOE genotype associates with different dementia types, and the association of this genotype with mild cognitive impairment and age related cognitive decline, which might be stages in a continuum between normality and dementia. From a group of 1,022 people we selected 733 patients with different dementia diagnosis and 205 controls. APOE genotype for each participant in the study was determined. As it was already known, the epsilon4 allele is associated to senile Alzheimer's disease (OR= 5.6; 95% CI= 3.6-8.9; p< 0.001) and presenile Alzheimer's disease (OR= 5.4; 95% CI= 2.1-13.8; p< 0.001). It is also associated to mild cognitive impairment (OR= 3.7; 95% CI= 2.3-6.0; p< 0.001) and to age related cognitive decline (OR= 3.0; 95% CI= 1.2-7.3; p< 0.01). Female Alzheimer patients with at least one epsilon4 allele present significantly an earlier age at onset (epsilon4+= 73.4 +/- 5.4; epsilon4- = 76.9 +/- 5.5; p< 0.001). The APOE genotype is associated to Alzheimer's disease and to its cognitive impairment pattern. This association has a growing value according to the degree of clinical impairment. The APOE genotype could be used in differential diagnostic of cognitive impairment.

BetaAPP and furin mRNA concentrates in immature senile plaques in the brain of Alzheimer patients.

This study examined the possibility that in Alzheimer disease (AD) beta-amyloid precursor protein (betaAPP) mRNA is delivered to senile plaques (SPs) via dendritic processes. BetaAPP mRNA was detected in SPs by in situ hybridization, using a 1.4-kb cRNA in which both [35S]-UTP and [35S]-CTP were incorporated together. The betaAPP mRNA was compared with that of furin, a proteolytic enzyme putatively involved in betaAPP processing, and its orthologue proprotein convertase PCI served as a control. Human presenile AD cases with mostly immature SPs and AD cases generally with mature SPs were analyzed. To decrypt SPs after hybridization, brain sections were stained with thioflavin S. To establish relationships between the density of dystrophic fibers, the degree of plaque maturation, and the concentration of mRNA in SPs, the plaque maturity markers Abeta(1-42) and Abeta(1-40) peptides were co-localized with neurofilament protein 200 and compared with microtubule-associated protein 2 (MAP 2). The results suggest that immature, Abeta(1-42)- and dystrophic dendrite-containing SPs (but not mature SPs containing Abeta(1-40) and missing dystrophic dendrites) are capable of concentrating specific mRNAs. Dystrophic dendrites may thus serve as a route for the transport of specific mRNAs from the cell bodies to SPs.

Amyloid β secretase gene (BACE) is neither mutated in nor associated with early-onset Alzheimer's disease

The beta-site of β-amyloid precursor protein cleaving enzyme (BACE) cleaves the β-amyloid (A β) precursor protein at the N-terminal end of A β, allowing for the production of A β by C-terminal γ-secretase cleavage. We hypothesized that over-activity of BACE might lead to the overproduction of A β, hence causing Alzheimer's disease (AD). Molecular genetic analyses of BACE in 9 autosomal dominant AD families and a population-based sample of 101 presenile AD cases did not identify genetic linkage, pathogenic mutations or genetic association with BACE, suggesting that BACE is not genetically involved in the etiology of AD.

Autoantibodies to beta-amyloid and neurotransmitters in patients with Alzheimer's disease and senile dementia of the Alzheimer type.

The content of autoantibodies to beta-amyloid protein Abeta(1-42), its neurotoxic fragment Abeta(25-35), and neurotransmitters were studied in the blood of patients with presenile Alzheimer's disease and senile dementia of the Alzheimer type. Significant differences in the relative content of autoantibodies to Abeta(1-42)and autoantibodies to biogenic amines were demonstrated. These results can be used for the development of a biochemical method for differential diagnosis of Alzheimer dementias.

A novel missense mutation (L219F) in exon 8 of the presenilin 1 gene in an italian family with presenile familial Alzheimer's disease

A novel missense mutation (L219F) in exon 8 of the presenilin 1 gene in an italian family with presenile familial Alzheimer's disease

Tau Pathology Generated by Overexpression of Tau

Neurofibrillary changes of abnormally hyperphosphorylated tau are the key lesion in Alzheimer’s disease (AD) and a number of other tauopathies. Recent developments in the field of autosomal dominantly inherited dementias, in particular the frontotemporal dementias and Parkinsonism linked to chromosome 17 (FTDP-17) group, have shown that abnormalities in the tau gene result in neurofibrillary degeneration and cell death. Clinically this disorder presents with behavioral abnormalities, which are followed by dementia and, depending on the affected areas, by motor dysfunction. The location of the lesions does not seem to depend so much on the type of mutation as on the individual’s genetic background and may vary even in the same family with the identical mutation. For instance, in one family with a P 301 S mutation in exon 10 of tau, the father presented with frontotemporal dementia, whereas the son had corticobasal degeneration. 1 FTDP-17 is associated with both exonic and intronic mutations of the tau gene. The microtubule-associated protein (MAP) tau is a family of six proteins derived by alternative mRNA splicing 2,3 from a single gene located on chromosome 17. These molecular isoforms of tau differ in whether they contain three or four tubulin binding domains/repeats of 31 or 32 amino acids each near the C-terminal end and no, one, or two inserts of 29 amino acids each at the N-terminal end of the molecule. There are nine missense mutations on tau exons 9 to 13; all but three are on exon 10. 4-7 Exon 10 codes for the additional insert of the three 4-repeat tau isoforms. The resulting mutated taus possess an altered conformation 8 and a somewhat reduced ability to bind to and assemble microtubules. 9,10 In addition to the exonic mutations, mutations at several sites have been found in the predicted stem loop structure in the 5′ splice site to exon 10. These intronic mutations and certain mutations in exon 10 that are close to the stem loop, and thus able to disrupt it, lead to two- to sixfold higher proportion of tau mRNA containing exon 10 than in control brains. 5 The tau protein resulting from intronic mutations is normal, but the ratio of 4-repeat to 3-repeat isoforms is increased. Presently it is believed that due to the increased proportion of 4-repeat tau in the case of intronic mutations and the compromised biological activity of the tau with missense mutations, excess tau is not bound to the microtubules, which can then be hyperphosphorylated and would lead to neurofibrillary degeneration. In contrast to the FTDP-17 group of diseases, no mutations in the tau gene have been reported in AD at the time of writing this Commentary. In more than 90% of the AD patients the disease occurs sporadically above 60 years of age. In less than 5% of the cases the disease segregates with mutations in the amyloid precursor protein (APP), presenilin-1 (PS-1), or presenilin-2 (PS-2) genes. 11 Frameshift mutations of APP and ubiquitin at the level of transcription have been reported to be associated with sporadic and familial AD and Down’s syndrome. 12 The occurrence of the apolipoprotein E4 allele 13 and, most recently, mutations in the β2 macroglobulin gene 14 have been reported to be risk factors for the development of the late onset, sporadic AD. AD has two prominent neuropathological lesions, the extracellular deposits of the amyloid β peptide (Aβ) as plaques and the intraneuronal paired helical filaments (PHF) of abnormally hyperphosphorylated tau, which accumulate in the neuronal cell body as neurofibrillary tangles, in the neuropil (the so-called neuropil threads), 15 and in the dystrophic neurites surrounding the neuritic plaques. The direct relationship, if any, between the tangles and β-amyloid is not yet understood. At the one extreme, in the normal aged brain there is the significant β-amyloid accumulation and minimal neurofibrillary degeneration, whereas in the early onset familial AD with mutations in the β-APP or presenilin gene, massive β-amyloid deposits, tau hyperphosphorylation, and tangle formation are always seen. The other extreme situation is represented by extensive neurofibrillary degeneration and minimal β-amyloidosis. These include tauopathies like the tangle-predominant form of senile dementia (tangle-only dementia), Guam Parkinsonism dementia complex, dementia with argyrophilic grains, Nieman Pick’s disease type C, subacute sclerosing panencephalitis, Pick’s disease, and the dementia group with mutations in the tau gene. 16 Although at present the exact role of PHF and β-amyloid in the pathogenesis of AD is not established, there is growing evidence from a number of laboratories that the intellectual deterioration in AD patients is associated with neurofibrillary degeneration. 17-20 A third and well characterized phenomenon is synaptic loss and cell death exceeding 50% in certain areas of the brain. 21,22